Chemical compounds 572

ABSTRACT

Compounds of formula (I): 
                         
The present invention relates to novel indazolyl ester or amide derivatives, to pharmaceutical compositions comprising such derivatives, to processes for preparing such novel derivatives and to the use of such derivatives as medicaments.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/643,504 filed on Dec. 21, 2009 now abandoned, which is a continuationof U.S. application Ser. No. 12/005,066 filed on Dec. 20, 2007 now U.S.Pat. No. 7,728,030, which claims the benefit under 35 U.S.C. §119(e) ofU.S. Provisional Application No. 60/978,526, filed on Oct. 9, 2007, U.S.Provisional Application No. 60/941,745, filed on Jun. 4, 2007, and U.S.Provisional Application No. 60/871,184, filed on Dec. 21, 2006; each ofthese prior applications is incorporated herein by reference in itsentirety.

The present invention relates to novel indazolyl ester or amidederivatives, to pharmaceutical compositions comprising such derivatives,to processes for preparing such novel derivatives and to the use of suchderivatives as medicaments (for example in the treatment of aninflammatory disease state).

Sulphonamide derivatives are disclosed as anti-inflammatories in WO2004/019935 and WO 2004/050631. Pharmaceutically active sulphonamidesare also disclosed in Arch. Pharm. (1980) 313 166-173, J. Med. Chem.(2003) 46 64-73, J. Med. Chem. (1997) 40 996-1004, EP 0031954, EP1190710 (WO 200124786), U.S. Pat. No. 5,861,401, U.S. Pat. No.4,948,809, U.S. Pat. No. 3,992,441 and WO 99/33786.

It is known that certain non-steroidal compounds interact with theglucocorticoid receptor (GR) and, as a result of this interaction,produce a suppression of inflammation (see, for example, U.S. Pat. No.6,323,199). Such compounds can show a clear dissociation betweenanti-inflammatory and metabolic actions making them superior to earlierreported steroidal and non-steroidal glucocorticoids. The presentinvention provides further non-steroidal compounds as modulators (forexample agonists, antagonists, partial agonists or partial antagonists)of the glucocorticoid receptor.

These new compounds are contemplated to have improved properties such asselectivity, efficacy, etc. over the known compounds.

The present invention provides a compound of formula (I):

wherein:A is C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆cyanoalkyl, cyano, C₁₋₆nitroalkyl,nitro, C₁₋₄alkylS(O)_(n), C₁₋₆alkoxy, C₃₋₇cycloalkylC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇heterocycloalkyl, C₃₋₇heterocycloalkylC₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkyl, C₁₋₆thioalkyl, C₁₋₆thioalkyl,C₁₋₆alkylOC₁₋₆alkyl, C₁₋₄alkylOC₁₋₆alkylOC₁₋₆alkyl,C₁₋₆alkylOC₁₋₆alkylO, C₁₋₄alkylC(O)C₁₋₆alkyl, C₁₋₆alkylC(O),C₁₋₆alkylC(O)OC₁₋₆-alkyl, C₁₋₆alkylC(O)O, C₁₋₆alkylOC(O)C₁₋₆alkyl,C₁₋₆alkylOC(O), HOC(O), NR⁵R⁶C₁₋₆alkyl, NR⁵R⁶, NR⁵R⁶C(O)C₁₋₆alkyl,NR⁵R⁶C(O), NR⁵R⁶OC(O)C₁₋₆alkyl, NR⁵R⁶OC(O), R⁷NH, C₅₋₁₀arylC₁₋₃alkyl,C₅₋₁₀aryl, C₅₋₁₀heteroarylC₁₋₃alkyl or C₅₋₁₀heteroaryl, whereby thecycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionallysubstituted by one or more substituents independently selected fromhalo, cyano, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl,C₁₋₄alkylOC(O), C₁₋₄alkylOC₁₋₄alkyl, C₁₋₄alkylS(O)₂ and C₁₋₄haloalkylO,and R^(x) is hydrogen, orA forms together with R^(x) a 5 to 6 membered azacyclic ring optionallyhaving one or more further heteroatoms independently selected from O, Nand S;R¹ and R^(1a) are independently selected from hydrogen, C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkylOC₁₋₄alkyl, C₁₋₄alkylC₁₋₄thioalkyl andC₁₋₄haloalkyl, or R¹ and R^(1a) together are oxo;R² is hydrogen or C₁₋₄alkyl;R³ is C₅₋₁₀aryl, C₅₋₁₀arylC₁₋₄alkyl, C₅₋₁₀arylO, C₅₋₁₀arylOC₁₋₄alkyl orC₅₋₁₀heteroaryl, which may be optionally substituted by one or moresubstituents independently selected from B;B is C₁₋₃hydroxyalkyl, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkylC₁₋₄thioalkyl, C₁₋₄thioalkyl, C₃₋₆cycloalkylC₁₋₄thioalkyl,C₃₋₆cycloalkylS, C₁₋₃alkylS(O)_(n)C₁₋₄alkyl, C₁₋₃alkylS(O)_(n),C₁₋₄haloalkyl, C₁₋₄haloalkylO, halo, nitro, cyano,C₁₋₄alkylOC₁₋₄alkylOC₁₋₄alkyl, C₁₋₄alkylC(O)C₁₋₄alkyl, C₁₋₄alkylC(O),C₁₋₄alkylC(O)OC₁₋₄alkyl, C₁₋₄alkylC(O)O, C₁₋₄alkylOC(O)C₁₋₄alkyl,C₁₋₄alkylOC(O), NR⁸R⁹C₁₋₄alkyl, NR⁸R⁹, NR⁸R⁹C(O)C₁₋₄alkyl, NR⁸R⁹C(O),NR⁸R⁹OC(O)C₁₋₄alkyl, NR⁸R⁹OC(O)O, NR⁸R⁹C(O)OC₁₋₄alkyl, NR⁸R⁹C(O)O,R⁹C(O)R⁸NC₁₋₄alkyl, R⁹C(O)R⁸NH, C₁₋₄alkylNH, C₁₋₄alkylOC(O)NH,C₁₋₄alkylC(O)OC₁₋₄alkylNH, C₁₋₄alkylC(O)C₁₋₄alkylNH, C₁₋₄alkylC(O)NH,NR⁸R⁹S(O)_(n)C₁₋₄alkyl or NR⁸R⁹S(O)_(n);n is 1 or 2;R⁴ is hydrogen, hydroxy, halo, C₁₋₄alkyl or C₁₋₄haloalkyl;W is hydrogen, orphenyl, C₁₋₄alkyl, C₃₋₇cycloalkyl, thienyl, isoxazolyl, pyrazolyl,pyridinyl, pyridazinyl or pyrimidinyl all of which are optionallysubstituted by one or more substituents independently selected fromC₁₋₃hydroxyalkyl, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkylC₁₋₄thioalkyl, C₁₋₄thioalkyl, C₃₋₆cycloalkylC₁₋₄thioalkyl,C₃₋₆cycloalkylS, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₄alkyl,C₃₋₆heterocycloalkyl, C₃₋₆heterocycloalkylC₁₋₄alkyl,C₁₋₄alkylS(O)_(n)C₁₋₄alkyl, C₁₋₄alkylS(O)_(n), C₁₋₄haloalkyl,C₁₋₄haloalkylO, halo, nitro, cyano, C₁₋₄alkylOC₁₋₄alkyl,C₁₋₄alkylOC₁₋₄alkylOC₁₋₄alkyl, C₁₋₄alkylC(O)C₁₋₄alkyl, C₁₋₄alkylC(O),C₁₋₄alkylC(O)OC₁₋₄alkyl, C₁₋₄alkylC(O)O, C₁₋₄alkylOC(O)C₁₋₄alkyl,C₁₋₄alkylOC(O), NR¹⁰R¹¹C₁₋₄alkyl, NR¹⁰R¹¹, NR¹⁰R¹¹C(O)C₁₋₄alkyl,NR¹⁰R¹¹C(O), NR¹⁰R¹¹C(O)OC₄alkyl, NR¹⁰R¹¹C(O)O, NR¹⁰R¹¹OC(O)C₁₋₄alkyl,NR¹⁰R¹¹OC(O), R¹¹C(O)R¹⁰NC₁₋₄alkyl, R¹¹C(O)R¹⁰NH,C₁₋₄alkylOC(O)C₁₋₄alkylNH, C₁₋₄alkylOC(O)NH, C₁₋₄alkylC(O)OC₁₋₄alkylNH,C₁₋₄alkylC(O)C₁₋₄alkylNH, C₁₋₄alkylC(O)NH, NR¹⁰R¹¹S(O)_(n)C₁₋₄alkyl orNR¹⁰R¹¹S(O)_(n);X is CH₂, O, S, S(O)_(n), NH or NC₁₋₄alkyl;Y is hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄thioalkyl,C₁₋₄haloalkyl, C₁₋₄ haloalkylO, nitro, cyano, hydroxy, R¹²C(O),R¹²OC(O), R¹²C(O)O, C₁₋₆alkylS(O)_(n), R¹²R¹³NS(O)_(n), benzyloxy,imidazolyl, C₁₋₄alkylNHC(O), NR¹²R¹³C(O), C₁₋₄alkylC(O)NH or NR¹²R¹³;Z is O or S;R⁵, R⁶, R⁸, R⁹, R¹⁰R¹¹, R¹² and R¹³ are independently selected fromhydrogen, C₁₋₆alkylC(O), NHR⁷C(O) and C₁₋₆alkyl; andR⁷ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylC(O)OC₁₋₃alkyl, C₁₋₆alkylC(O)O,C₁₋₆alkylOC(O)C₁₋₃alkyl, C₁₋₆alkylOC(O), C₁₋₆alkylC(O),C₅₋₁₀heteroarylC₁₋₃alkyl, C₅₋₁₀heteroaryl, C₅₋₁₀arylC₁₋₃alkyl,C₅₋₁₀aryl, C₃₋₆cycloalkylC₁₋₃alkyl or C₃₋₆cycloalkyl;or a pharmaceutically acceptable salt thereof.

One embodiment of the invention related to compounds of formula Iwherein:

A is C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆cyanoalkyl, cyano, C₁₋₆nitroalkyl,nitro, C₁₋₆alkylS(O)_(n), C₁₋₆alkoxy, C₃₋₇cycloalkylC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇heterocycloalkyl, C₃₋₇heterocycloalkylC₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkylC₁₋₆thioalkyl, C₁₋₆thioalkyl,C₁₋₆alkylOC₁₋₆alkyl, C₁₋₆alkylOC₁₋₆alkylOC₁₋₆alkyl,C₁₋₆alkylOC₁₋₆alkylO, C₁₋₆alkylC(O)C₁₋₆alkyl, C₁₋₆alkylC(O),C₁₋₆alkylC(O)OC₁₋₆alkyl, C₁₋₆alkylC(O)O, C₁₋₆alkylOC(O)C₁₋₆alkyl,C₁₋₆alkylOC(O), HOC(O), NR⁵R⁶C₁₋₆alkyl, NR⁵R⁶, NR⁵R⁶C(O)C₁₋₆alkyl,NR⁵R⁶C(O), NR⁵R⁶OC(O)C₁₋₆alkyl, NR⁵R⁶OC(O), R⁷NH, C₅₋₁₀arylC₁₋₃alkyl,C₅₋₁₀aryl, C₅₋₁₀heteroarylC₁₋₃alkyl or C₅₋₁₀heteroaryl, whereby thecycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionallysubstituted by one or more substituents independently selected fromhalo, cyano, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl,C₁₋₄alkylOC(O), C₁₋₄alkylOC₁₋₄alkyl, C₁₋₄alkylS(O)₂ and C₁₋₄haloalkylO,and R^(x) is hydrogen, orA forms together with R^(x) a 5 to 6 membered azacyclic ring optionallyhaving one or more further heteroatoms independently selected from O, Nand S;R¹ and R^(1a) are independently selected from hydrogen, C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkylOC₁₋₄alkyl, C₁₋₄alkylC₁₋₄thioalkyl andC₁₋₄haloalkyl, or R¹ and R^(1a) together are oxo;R² is hydrogen or C₁₋₄alkyl;R³ is C₅₋₁₀aryl, C₅₋₁₀arylC₁₋₄alkyl, C₅₋₁₀arylO, C₅₋₁₀arylOC₁₋₄alkyl orC₅₋₁₀heteroaryl, which may be optionally substituted by one or moresubstituents independently selected from B;B is C₁₋₃hydroxyalkyl, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkylC₁₋₄thioalkyl, C₁₋₄thioalkyl, C₃₋₆cycloalkylC₁₋₄thioalkyl,C₃₋₆cycloalkylS, C₁₋₃alkylS(O)_(n)C₁₋₄alkyl, C₁₋₃alkylS(O)_(n),C₁₋₄haloalkyl, C₁₋₄haloalkylO, halo, nitro, cyano,C₁₋₄alkylOC₁₋₄alkylOC₁₋₄alkyl, C₁₋₄alkylC(O)C₁₋₄alkyl, C₁₋₄alkylC(O),C₁₋₄alkylC(O)OC₁₋₄alkyl, C₁₋₄alkylC(O)O, C₁₋₄alkylOC(O)C₁₋₄alkyl,C₁₋₄alkylOC(O), NR⁸R⁹C₁₋₄alkyl, NR⁸R⁹, NR⁸R⁹C(O)C₁₋₄alkyl, NR⁸R⁹C(O),NR⁸R⁹OC(O)C₁₋₄alkyl, NR⁸R⁹OC(O), NR⁸R⁹C(O)OC₁₋₄alkyl, NR⁸R⁹C(O)O,R⁹C(O)R⁸NC₁₋₄alkyl, R⁹C(O)R⁸NH, C₁₋₄alkylNH, C₁₋₄alkylOC(O)NH,C₁₋₄alkylC(O)OC₁₋₄alkylNH, C₁₋₄alkylC(O)C₁₋₄alkylNH, C₁₋₄alkylC(O)NH,NR⁸R⁹S(O)_(n)C₁₋₄alkyl or NR⁸R⁹S(O)_(n);n is 1 or 2;R⁴ is hydrogen, hydroxy, halo, C₁₋₄alkyl or C₁₋₄haloalkyl;W is phenyl, C₁₋₄alkyl, C₃₋₇cycloalkyl, thienyl, isoxazolyl, pyrazolyl,pyridinyl, pyridazinyl or pyrimidinyl all of which are optionallysubstituted by one or more substituents independently selected fromC₁₋₃hydroxyalkyl, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkylC₁₋₄thioalkyl, C₁₋₄thioalkyl, C₃₋₆cycloalkylC₁₋₄thioalkyl,C₃₋₆cycloalkylS, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₄alkyl,C₃₋₆heterocycloalkyl, C₃₋₆heterocycloalkylC₁₋₄alkyl,C₁₋₄alkylS(O)_(n)C₁₋₄alkyl, C₁₋₄alkylS(O)_(n), C₁₋₄haloalkyl,C₁₋₄haloalkylO, halo, nitro, cyano, C₁₋₄alkylOC₁₋₄alkyl,C₁₋₄alkylOC₁₋₄alkylOC₁₋₄alkyl, C₁₋₄alkylC(O)C₁₋₄alkyl, C₁₋₄alkylC(O),C₁₋₄alkylC(O)OC₁₋₄alkyl, C₁₋₄alkylC(O)O, C₁₋₄alkylOC(O)C₁₋₄alkyl,C₁₋₄alkylOC(O), NR¹⁰R¹¹C₁₋₄alkyl, NR¹⁰R¹¹, NR¹⁰R¹¹C(O)C₁₋₄alkyl,NR¹⁰R¹¹C(O), NR¹⁰R¹¹C(O)OC₁₋₄alkyl, NR¹⁰R¹¹C(O)O, NR¹⁰R¹¹OC(O)C₁₋₄alkyl,NR¹⁰R¹¹OC(O), R¹¹C(O)R¹⁰NC₁₋₄alkyl, R¹¹C(O)R¹⁰NH,C₁₋₄alkylOC(O)C₁₋₄alkylNH, C₁₋₄alkylOC(O)NH, C₁₋₄alkylC(O)OC₁₋₄alkylNH,C₁₋₄alkylC(O)C₁₋₄alkylNH, C₁₋₄alkylC(O)NH, NR¹⁰R¹¹S(O)_(n)C₁₋₄alkyl orNR¹⁰R¹¹S(O)_(n);X is CH₂, O, S, S(O)_(n), NH or NC₁₋₄alkyl;Y is hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄thioalkyl,C₁₋₄haloalkyl, C₁₋₄ haloalkylO, nitro, cyano, hydroxy, R¹²C(O),R¹²OC(O), R¹²C(O)O, C₁₋₆alkylS(O)_(n), R¹²R¹³NS(O)_(n), benzyloxy,imidazolyl, C₁₋₄alkylNHC(O), NR¹²R¹³C(O), C₁₋₄alkylC(O)NH or NR¹²R¹³;Z is O or S;R⁵, R⁶, R⁸, R⁹, R¹⁰ R¹¹, R¹² and R¹³ are independently selected fromhydrogen, C₁₋₆alkylC(O), NHR⁷C(O) and C₁₋₆alkyl; andR⁷ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylC(O)OC₁₋₃alkyl, C₁₋₆alkylC(O)O,C₁₋₆alkylOC(O)C₁₋₃alkyl, C₁₋₆alkylOC(O), C₁₋₆alkylC(O),C₅₋₁₀heteroarylC₁₋₃alkyl, C₅₋₁₀heteroaryl, C₅₋₁₀arylC₁₋₃alkyl,C₅₋₁₀aryl, C₃₋₆cycloalkylC₁₋₃alkyl or C₃₋₆cycloalkyl;or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention related to compounds of formula Iwherein:

A is R⁷NH, and R^(x) is hydrogen;

R¹ and R^(1a) are independently selected from hydrogen, C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkylOC₁₋₄alkyl, C₁₋₄alkylC₁₋₄thioalkyl andC₁₋₄haloalkyl, or R¹ and R^(1a) together are oxo;

R² is hydrogen or C₁₋₄alkyl;

R³ is C₅₋₁₀aryl, C₅₋₁₀arylC₁₋₄alkyl, C₅₋₁₀arylO, C₅₋₁₀arylOC₁₋₄alkyl orC₅₋₁₀heteroaryl, which may be optionally substituted by one or moresubstituents independently selected from B;

B is C₁₋₃hydroxyalkyl, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkylC₁₋₄thioalkyl, C₁₋₄thioalkyl, C₃₋₆cycloalkylC₁₋₄thioalkyl,C₃₋₆cycloalkylS, C₁₋₃alkylS(O)_(n)C₁₋₄alkyl, C₁₋₃alkylS(O)_(n),C₁₋₄haloalkyl, C₁₋₄haloalkylO, halo, nitro, cyano,C₁₋₄alkylOC₁₋₄alkylOC₁₋₄alkyl, C₁₋₄alkylC(O)C₁₋₄alkyl, C₁₋₄alkylC(O),C₁₋₄alkylC(O)OC₁₋₄alkyl, C₁₋₄alkylC(O)O, C₁₋₄alkylOC(O)C₁₋₄alkyl,C₁₋₄alkylOC(O), NR⁸R⁹C₁₋₄alkyl, NR⁸R⁹, NR⁸R⁹C(O)C₁₋₄alkyl, NR⁸R⁹C(O),NR⁸R⁹OC(O)C₁₋₄alkyl, NR⁸R⁹OC(O), NR⁸R⁹C(O)OC₁₋₄alkyl, NR⁸R⁹C(O)O,R⁹C(O)R⁸NC₁₋₄alkyl, R⁹C(O)R⁸NH, C₁₋₄alkylNH, C₁₋₄alkylOC(O)NH,C₁₋₄alkylC(O)OC₁₋₄alkylNH, C₁₋₄alkylC(O)C₁₋₄alkylNH, C₁₋₄alkylC(O)NH,NR⁸R⁹S(O)_(n)C₁₋₄alkyl or NR⁸R⁹S(O)_(n);n is 1 or 2;R⁴ is hydrogen, hydroxy, halo, C₁₋₄alkyl or C₁₋₄haloalkyl;W is phenyl, C₁₋₄alkyl, C₃₋₇cycloalkyl, thienyl, isoxazolyl, pyrazolyl,pyridinyl, pyridazinyl or pyrimidinyl all of which are optionallysubstituted by one or more substituents independently selected fromC₁₋₃hydroxyalkyl, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkylC₁₋₄thioalkyl, C₁₋₄thioalkyl, C₃₋₆cycloalkylC₁₋₄thioalkyl,C₃₋₆cycloalkylS, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₄alkyl,C₃₋₆heterocycloalkyl, C₃₋₆heterocycloalkylC₁₋₄alkyl,C₁₋₄alkylS(O)_(n)C₁₋₄alkyl, C₁₋₄alkylS(O)_(n), C₁₋₄haloalkyl,C₁₋₄haloalkylO, halo, nitro, cyano, C₁₋₄alkylOC₁₋₄alkyl,C₁₋₄alkylOC₁₋₄alkylOC₁₋₄alkyl, C₁₋₄alkylC(O)C₁₋₄alkyl, C₁₋₄alkylC(O),C₁₋₄alkylC(O)OC₁₋₄alkyl, C₁₋₄alkylC(O)O, C₁₋₄alkylOC(O)C₁₋₄alkyl,C₁₋₄alkylOC(O), NR¹⁰R¹¹C₁₋₄alkyl, NR¹⁰R¹¹, NR¹⁰R¹¹C(O)C₁₋₄alkyl,NR¹⁰R¹¹C(O), NR¹⁰R¹¹C(O)OC₁₋₄alkyl, NR¹⁰R¹¹C(O)O, NR¹⁰R¹¹OC(O)C₁₋₄alkyl,NR¹⁰R¹¹OC(O), R¹¹C(O)R¹⁰NC₁₋₄alkyl, R¹¹C(O)R¹⁰NH,C₁₋₄alkylOC(O)C₁₋₄alkylNH, C₁₋₄alkylOC(O)NH, C₁₋₄alkylC(O)OC₁₋₄alkylNH,C₁₋₄alkylC(O)C₁₋₄alkylNH, C₁₋₄alkylC(O)NH, NR¹⁰R¹¹S(O)_(n)C₁₋₄alkyl orNR¹⁰R¹¹S(O)_(n);X is CH₂, O, S, S(O)_(n), NH or NC₁₋₄alkyl;Y is hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄thioalkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylO, nitro, cyano, hydroxy, R¹²C(O), R¹²C(O),R¹²C(O)O, C₁₋₆alkylS(O)_(n), R¹²R¹³NS(O)_(n), benzyloxy, imidazolyl,C₁₋₄alkylNHC(O), NR¹²R¹³C(O), C₁₋₄alkylC(O)NH or NR¹²R¹³;Z is O or S;R⁵, R⁶, R⁸, R⁹, R¹⁰ R¹¹, R¹² and R¹³ are independently selected fromhydrogen, C₁₋₆alkylC(O), NHR⁷C(O) and C₁₋₆alkyl; andR⁷ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylC(O)OC₁₋₃alkyl, C₁₋₆alkylC(O)O,C₁₋₆alkylOC(O)C₁₋₃alkyl, C₁₋₆alkylOC(O), C₁₋₆alkylC(O),C₅₋₁₀heteroarylC₁₋₃alkyl, C₅₋₁₀heteroaryl, C₅₋₁₀arylC₁₋₃alkyl,C₅₋₁₀aryl, C₃₋₆cycloalkylC₁₋₃alkyl or C₃₋₆cycloalkyl;or a pharmaceutically acceptable salt thereof.

One embodiment of the invention related to compounds of formula Iwherein:

A is C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, C₃₋₇cycloalkyl,C₃₋₇heterocycloalkyl, C₁₋₆haloalkyl, C₁₋₆alkylOC₁₋₆alkyl,C₁₋₆alkylOC₁₋₆alkylOC₁₋₆alkyl, C₁₋₆alkylC(O)OC₁₋₆alkyl, C₁₋₆alkylOC(O),HOC(O), NR⁵R⁶C₁₋₆alkyl, NR⁵R⁶C(O), NR⁵R⁶OC(O), R⁷NH, C₅₋₁₀arylC₁₋₃alkyl,C₅₋₁₀aryl or C₅₋₁₀heteroaryl, whereby the cycloalkyl, heterocycloalkyl,aryl or heteroaryl may be optionally substituted by one or moresubstituents independently selected from halo, cyano, hydroxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, C₁₋₄alkylOC(O),C₁₋₄alkylOC₁₋₄alkyl and C₁₋₄alkylS(O)₂ and R^(x) is hydrogen, orA forms together with R^(x) a 5 membered azacyclic ring optionallyhaving one or more further heteroatoms independently selected from O andN;R¹ and R^(1a) are independently selected from hydrogen, C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkylOC₁₋₄alkyl and C₁₋₄haloalkyl, or R¹ andR^(1a) together are oxo;R² is hydrogen or C₁₋₄alkyl;R² is hydrogen;R³ is C₅₋₁₀aryl, C₅₋₁₀arylC₁₋₄alkyl, C₅₋₁₀arylO, C₅₋₁₀arylOC₁₋₄alkyl orC₅₋₁₀heteroaryl, which may be optionally substituted by one or moresubstituents independently selected from B;B is hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylC₁₋₄thioalkyl,C₁₋₄thioalkyl, C₃₋₆cycloalkylS, C₁₋₃alkylS(O)_(n)C₁₋₄alkyl,C₁₋₃alkylS(O)_(n), C₁₋₄haloalkyl or halo;n is 1 or 2;R⁴ is hydrogen;W is phenyl, C₁₋₄alkyl, C₃₋₇cycloalkyl, pyridinyl, pyridazinyl orpyrimidinyl all of which are optionally substituted by one or moresubstituents independently selected from C₁₋₃hydroxyalkyl,C₃₋₆heterocycloalkylC₁₋₄alkyl, halo, C₁₋₄alkylOC(O) andNR¹⁰R¹¹C₁₋₄alkyl;X is O or S;Y is hydrogen, halo or C₁₋₄alkyl;Z is O or S;R⁵, R⁶, R¹⁰ and R¹¹ are independently selected from hydrogen,C₁₋₆alkylC(O), NHR⁷C(O) and C₁₋₆alkyl; andR⁷ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylOC(O)C₁₋₃alkyl,C₅₋₁₀heteroarylC₁₋₃alkyl or C₃₋₆cycloalkyl;or a pharmaceutically acceptable salt thereof.

One embodiment of the invention related to compounds of formula Iwherein:

A is C₁₋₃hydroxyalkyl, C₃₋₅cycloalkyl, C₁₋₃haloalkyl or NR⁵R⁶C(O);

R¹ and R^(1a) are independently selected from hydrogen and C₁₋₃alkyl;

R² is hydrogen;

R³ is C₅₋₁₀aryl C₅₋₁₀arylOC₁₋₂alkyl or C₅₋₁₀heteroaryl, which may beoptionally substituted by one or more substituents independentlyselected from B;

B is C₁₋₃alkoxy or C₁₋₃alkylS(O)_(n);

n is 2;

R⁴ is hydrogen;

W is phenyl which is optionally substituted by one or more halo;

X is O;

Y is hydrogen;

Z is O;

R⁵ and R⁶ are independently selected from hydrogen and C₁₋₃alkyl; and

R^(X) is hydrogen;

or a pharmaceutically acceptable salt thereof.

One embodiment of the invention relates to compounds of formula Iwherein R¹, R^(1a), R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰ R¹¹, R¹², R¹³,R^(x), Y, W and n are as defined above, and A is R⁷NH and R⁷ ishydrogen, C₁₋₆alkyl, C₁₋₆alkylOC(O)C₁₋₃alkyl, C₅₋₁₀heteroarylC₁₋₃alkylor C₃₋₆cycloalkyl.

In yet a further embodiment relating to compounds of formula I R² ishydrogen; R⁴ is hydrogen; X is O; Y is hydrogen; and Z is O.

In one embodiment relating to compounds of formula I R¹ is C₁₋₄alkyl,R^(1a) is hydrogen, R² is hydrogen; R⁴ is hydrogen; X is O; Y ishydrogen; and Z is O.

In yet another embodiment relating to compounds of formula I R² ishydrogen; R⁴ is hydrogen; W is phenyl which is optionally substituted byone or more fluoro; X is O; Y is hydrogen; and Z is O.

In one embodiment relating to compounds of formula I A is C₁₋₆alkyl,C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, C₃₋₇cycloalkyl, C₃₋₇heterocycloalkyl,C₁₋₆haloalkyl, C₁₋₆alkylOC₁₋₆alkyl, C₁₋₆alkylOC₁₋₆-alkylOC₁₋₆alkyl,C₁₋₆alkylC(O)OC₁₋₆alkyl, C₁₋₆alkylOC(O), HOC(O), NR⁵R⁶C₁₋₆alkyl,NR⁵R⁶C(O), NR⁵R⁶OC(O), R⁷NH, C₅₋₁₀arylC₁₋₃alkyl, C₅₋₁₀aryl orC₅₋₁₀heteroaryl, whereby the cycloalkyl, heterocycloalkyl, aryl orheteroaryl may be optionally substituted by one or more substituentsindependently selected from halo, cyano, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄haloalkyl, C₁₋₄alkylOC(O), C₁₋₄alkylOC₁₋₄alkyl and C₁₋₄alkylS(O)₂and R^(x) is hydrogen, or

A forms together with Rx a 5 membered azacyclic ring optionally havingone or more further heteroatoms independently selected from O and N; and

R⁵, R⁶, R⁸, R⁹, R¹⁰ R¹¹, R¹² and R¹³ are independently selected fromhydrogen, C₁₋₆alkylC(O), NHR⁷C(O) and C₁₋₆alkyl; and

R⁷ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylC(O)OC₁₋₃alkyl, C₁₋₆alkylC(O)O,C₁₋₆alkylOC(O)C₁₋₃alkyl, C₁₋₆alkylOC(O), C₁₋₆alkylC(O),C₅₋₁₀heteroarylC₁₋₃alkyl, C₅₋₁₀heteroaryl, C₅₋₁₀arylC₁₋₃alkyl,C₅₋₁₀aryl, C₃₋₆cycloalkylC₁₋₃alkyl or C₃₋₆cycloalkyl.

In one embodiment relating to compounds of formula I A isC₃₋₇cycloalkyl. In another embodiment A is cyclopropanyl, cyclobutanylor cyclopentanyl. In a further embodiment A is C₃₋₇cycloalkylsubstituted with hydroxy or methyl.

In one embodiment relating to compounds of formula I A isC₃₋₇heterocycloalkyl. In another embodiment A is pyrrolidinyl optionallysubstituted with tert-butyl-carboxylate.

In a further embodiment relating to compounds of formula I A is methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl,i-pentyl, neo-pentyl, n-hexyl or i-hexyl. In one embodiment A is methyl,ethyl, n-propyl, i-propyl or i-butyl,

In one embodiment relating to compounds of formula I A is C₁₋₂haloalkyl.In another embodiment A is fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl,fluoropropyl, difluoropropyl, trifluoropropyl, chloromethyl,dichloromethyl, trichloromethyl or fluorochloromethyl.

In a further embodiment relating to compounds of formula I A isC₁₋₃hydroxyalkyl. In one embodiment A is hydroxymethyl, hydroxyethyl,hydroxy-i-propyl, hydroxy-n-propy, hydroxy-n-butyl, hydroxy-i-butyl,hydroxy-s-butyl or hydroxy-t-butyl.

In yet a further embodiment relating to compounds of formula I A isC₁₋₂alkoxy. In one embodiment A is methoxy.

In an alternative embodiment relating to compounds of formula I A isC₁₋₃alkylOC₁₋₃alkyl. In one embodiment A is methoxymethyl, methylethoxyor ethylmethoxy.

In another embodiment relating to compounds of formula I A isC₁₋₂alkylC(O)OC₁₋₂alkyl. In a further embodiment A ismethylethoxymethyl.

In yet another embodiment relating to compounds of formula I A ist-butyl-OC(O), n-butyl-OC(O), i-propyl-OC(O), n-propyl-OC(O),ethyl-OC(O), methyl-OC(O) or HOC(O).

In one embodiment relating to compounds of formula I A isC₅₋₁₀arylC₁₋₃alkyl or C₅₋₁₀aryl. In another embodiment A is phenyl. Inyet a further embodiment A is phenyl substituted with trifluoromethyl.In a further embodiment A is phenylC₁₋₃alkyl. In another embodiment A isbenzyl.

In another embodiment relating to compounds of formula I A isC₅₋₁₀heteroarylC₁₋₃alkyl or C₅₋₁₀heteroaryl. In one embodiment A isoxazolyl, furanyl, thiophene, pyrimidinyl, thiazolyl, pyrazolyl,pyrrolyl, imidazolyl, triazolyl, oxadiazolyl, benzoimidazolyl,benzothiophene, benzothiazolyl, imidazolidine-2,4-dione,pyrazolo[1,5-a]pyridinyl or pyridinyl optionally substituted with one ormore substituents independently selected from hydroxy, C₁₋₃alkyl,C₁₋₃alkoxy, C₁₋₄alkylOC(O), C₁₋₃haloalkyl, C₁₋₃alkylOC₁₋₃alkyl, cyano,halo or C₁₋₃alkylS(O)₂.

In one embodiment A is thiazolyl substituted with methyl.

In yet another embodiment relating to compounds of formula I A formstogether with R^(x) a 5 membered azacyclic ring optionally having one ormore further heteroatoms independently selected from O and N. In oneembodiment A forms together with R^(x) an imidazolidine-2,4-dione group.

In a further embodiment relating to compounds of formula I A isNR⁵R⁶C₁₋₄alkyl or NR⁵R⁶.

In one embodiment relating to compounds of formula I A is propanamide orbutanamide. In a further embodiment relating to compounds of formula I Ais R⁶NH— wherein R⁶ is NH₂C(O)—. In an alternative embodiment relatingto compounds of formula I A is NR⁵R⁶C(O) and R⁵ and R⁶ are independentlyselected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, n-pentyl, i-pentyl and neo-pentyl. In one embodimentboth R⁵ and R⁶ are hydrogen. In another embodiment both R⁵ and R⁶ aremethyl. In a further embodiment R⁵ is hydrogen and R⁶ is methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl,i-pentyl or neo-pentyl.

In another embodiment relating to compounds of formula I A is R⁷NH. Inone embodiment R⁷ is furan-methyl-. In another embodiment R⁷ isC₁₋₂alkylOC(O)C₁₋₂alkyl. In a further embodiment R⁷ is cyclopentanyl. Inone embodiment R⁷ is dimethylpropyl. In another embodiment R⁷ isformamide.

In one embodiment relating to compounds of formula I R³ is C₅₋₁₀aryl,C₅₋₁₀arylC₁₋₄alkyl, C₅₋₁₀arylO, C₅₋₁₀arylOC₁₋₄alkyl or C₅₋₁₀heteroaryl,which may be optionally substituted by one or more substituentsindependently selected from B;

B is hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylC₁₋₄thioalkyl,C₁₋₄thioalkyl, C₃₋₆cycloalkylS, C₁₋₃alkylS(O)_(n)C₁₋₄alkyl,C₁₋₃alkylS(O)_(n), C₁₋₄haloalkyl or halo; and

n is 1 or 2.

In one embodiment relating to compounds of formula I R³ is phenyl. Inanother embodiment R³ is phenyl substituted with one or more B. In afurther embodiment R³ is phenyl substituted with one or moresubstituents independently selected from hydroxy, methoxy, ethoxy,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,trifluoromethyl, fluoro, chloro, methylsulfanyl, ethylsulfanyl,cyclopropylsulfanyl, methylsulfanylethyl, ethylsulfanylmethyl,ethylsulfinylmethyl, methylsulfinylethyl or methylsulfonyl. In anotherembodiment R³ is phenyl substituted with methoxy. In yet anotherembodiment R³ is phenyl substituted with fluoro, In one embodiment R³ isphenyl disubstituted with fluoro. In a further embodiment R³ is phenylsubstituted with chloro. In another embodiment R³ is phenyldisubstituted with fluoro and chloro. In yet another embodiment R³ isphenyl substituted with methyl. In one embodiment R³ is phenyl di- ortri-substituted with methyl. In yet a further embodiment R³ is phenyldisubstituted with methyl and fluoro. In another embodiment R³ is phenyldisubstituted with methyl and methoxy. In yet another embodiment R³ isphenyl disubstituted with fluoro and methoxy.

In one embodiment relating to compounds of formula I R³ isC₆arylC₁₋₂alkyl. In yet another embodiment R³ is benzyl.

In another embodiment relating to compounds of formula I R³ isphenoxymethyl.

In yet another embodiment relating to compounds of formula I R³ isnaphthalenyl.

In another embodiment relating to compounds of formula I R³ isC₅₋₁₀heteroaryl. In one embodiment R³ is 3-pyridinyl or 4-pyridinylsubstituted with methoxy. In a further embodiment R³ isdioxabicyclodecatrienyl. In another embodiment R³ is quinolinyl. In oneembodiment R³ is dihydrobenzofuranyl.

In one embodiment relating to compounds of formula I W is phenylsubstituted with halo. In another embodiment W is phenyl substitutedwith fluoro. In yet another embodiment W is phenyl para substituted withfluoro. In a further embodiment W is phenyl substituted with chloro. Inone embodiment W is phenyl substituted with methylOC(O)—. In a furtherembodiment W is phenyl substituted with dimethylaminomethyl. In oneembodiment W is phenyl substituted with hydroxymethyl.

In another embodiment W is phenyl substituted with morpholinylmethyl.

In yet another embodiment relating to compounds of formula I W isbenzoate.

In a further embodiment relating to compounds of formula I W ispyridinyl, pyridazinyl or pyrimidinyl. In another embodiment W ispyridazinyl substituted with halo.

In one embodiment relating to compounds of formula I W is cyclopentanyl.In another embodiment relating to compounds of formula I W is n-propyl.

In one embodiment relating to compounds of formula I X is O. In anotherembodiment X is S.

In one embodiment relating to compounds of formula I Z is O. In anotherembodiment Z is S.

In one embodiment relating to compounds of formula I R^(1a) is hydrogen.

In another embodiment relating to compounds of formula I R¹ is methyl,ethyl or n-propyl, i-propyl, n-butyl or i-butyl. In a further embodimentR¹ is methyl. In another embodiment R¹ is ethyl, n-propyl ormethylpropyl.

In a further embodiment relating to compounds of formula I R¹ ismethoxymethyl. In yet another embodiment relating to compounds offormula I R¹ is hydroxymethyl.

In another embodiment relating to compounds of formula I R¹ istrifluoromethyl.

In one embodiment relating to compounds of formula I R^(1a) and R¹ areoxo.

In one embodiment relating to compounds of formula I R² is hydrogen.

In one embodiment relating to compounds of formula I R⁴ is hydrogen.

In one embodiment relating to compounds of formula I Y is hydrogen. Inanother embodiment Y is halo. In a further embodiment Y is chloro. Inone embodiment Y is methyl.

A further embodiment of the invention related to compounds of formula Ib

wherein:A is C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₀₋₆cyanoalkyl, C₀₋₆nitroalkyl,C₁₋₆S(O)_(n)alkyl, C₁₋₆alkoxy, C₃₋₇cycloalkylC₀₋₆alkyl, C₁₋₆haloalkyl,C₀₋₆alkylthioC₀₋₆alkyl, C₁₋₆alkylOC₁₋₆alkyl,C₁₋₆alkylOC₁₋₆alkylOC₁₋₆alkyl, C₀₋₆alkylC(O)C₀₋₆alkyl,C₀₋₆alkylC(O)OC₀₋₆alkyl, C₀₋₆alkylOC(O)C₀₋₆alkyl, NR⁵R⁶C₀₋₆alkyl,NR⁵R⁶C(O)C₀₋₆alkyl, NR⁵R⁶OC(O)C₀₋₆alkyl, R⁷NH, C₅₋₁₀arylC₀₋₃alkyl orC₅₋₁₀heteroarylC₀₋₃alkyl, whereby the cycloalkyl, aryl or heteroaryl maybe optionally substituted by C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl,C₁₋₄haloalkoxy;R¹ and R^(1a) are independently selected from hydrogen, C₁₋₄ alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkylOC₁₋₄alkyl, C₁₋₄alkylSC₁₋₄alkyl and C₁₋₄haloalkyl;R² is hydrogen or C₁₋₄ alkyl;R³ is C₅₋₁₀arylC₀₋₃alkyl, C₅₋₁₀arylOC₀₋₃alkyl, C₅₋₁₀heteroarylC₀₋₃alkyl,C₁₋₆alkyl, C₁₋₆alkenyl or C₁₋₆alkynyl which may be optionallysubstituted by one or more B;B is C₀₋₃hydroxyalkyl, C₁₋₄alkyl, C₁₋₄alkoxy, C₀₋₄alkylthioC₀₋₄alkyl,C₃₋₆cycloalkylC₀₋₄thioalkyl, C₀₋₃alkylS(O)_(n)C₀₋₄alkyl, C₁₋₆haloalkyl,C₁₋₄haloalkoxy, halo, nitro, cyano, C₁₋₄alkylOC₁₋₆alkyl,C₁₋₆alkylOC₁₋₄alkylOC₁₋₄alkyl, C₀₋₆alkylC(O)C₀₋₄alkyl,C₀₋₄alkylC(O)OC₀₋₄alkyl, C₀₋₄alkylOC(O)C₀₋₄alkyl, NR⁵R⁶C₀₋₄alkyl,NR⁵R⁶C(O)C₀₋₄alkyl, NR⁵R⁶OC(O)C₀₋₄alkyl, NR⁵R⁶C(O)OC₀₋₄alkyl,R⁶C(O)R⁵NC₀₋₄alkyl, C₀₋₄alkylOC(O)C₀₋₄alkylNH,C₀₋₄alkylC(O)OC₀₋₄alkylNH, C₀₋₄alkylC(O)C₀₋₄alkylNH orNR⁵R⁶S(O)_(n)C₀₋₄alkyl;n is 0, 1 or 2;R⁴ is hydrogen, hydroxy, halogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl;W is hydrogen or phenyl, C₃₋₇cycloalkyl, thienyl, isoxazolyl, pyrazolyl,pyridinyl or pyrimidinyl all of which are optionally substituted by oneor more halo, C₀₋₃hydroxyalkyl, C₁₋₄alkyl, C₁₋₄alkoxy,C₀₋₄alkylthioC₀₋₄alkyl, C₃₋₆cycloalkylC₀₋₄thioalkyl,C₀₋₄alkylS(O)_(n)C₀₋₄alkyl, C₁₋₆haloalkyl, C₁₋₄haloalkoxy, halo, nitro,cyano, C₁₋₄alkylOC₁₋₆alkyl, C₁₋₆alkylOC₁₋₆alkylOC₁₋₆alkyl,C₀₋₆alkylC(O)C₀₋₆alkyl, C₀₋₄alkylC(O)OC₀₋₄alkyl,C₀₋₄alkylOC(O)C₀₋₄alkyl, NR⁵R⁶C₀₋₄alkyl, NR⁵R⁶C(O)C₀₋₄alkyl,NR⁵R⁶C(O)OC₀₋₄alkyl, NR⁵R⁶OC(O)C₀₋₄alkyl, R⁶C(O)R⁵NC₀₋₄alkyl,C₀₋₄alkylOC(O)C₀₋₄alkylNH, C₀₋₄alkylC(O)OC₀₋₄alkylNH,C₀₋₄alkylC(O)C₀₋₄alkylNH or NR⁵R⁶S(O)_(n)C₀₋₄alkyl;X is CH₂, O, S, S(O)_(n), NH or NC₁₋₄ alkyl;Y is hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄thioalkyl,C₁₋₄haloalkyl, C₁₋₄alkoxyhalo, nitro, cyano, hydroxy, R⁵C(O), R⁵OC(O),R⁵C(O)O, S(O)_(n)C₁₋₄alkyl, R⁵R⁶NS(O)_(n), benzyloxy, imidazolyl,C₁₋₄alkylNHC(O), NR⁵R⁶C(O), C₁₋₄alkylC(O)NH or NR⁵R⁶;Z is O or S;R⁵ and R⁶ are independently selected from hydrogen and C₁₋₆alkyl; andR⁷ is C₀₋₆alkylC(O)OC₀₋₃alkyl, C₀₋₆alkylOC(O)C₀₋₃alkyl,C₅₋₁₀heteroarylC₀₋₃alkyl, C₅₋₁₀arylC₀₋₃alkylNH orC₃₋₆cycloalkylC₀₋₃alkyl;or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides the individualcompound:

-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]cyclopropanecarboxamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]propanamide,    methyl    N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]carbamate,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-hydroxy-2-methyl-propanamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]acetamide,-   N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-hydroxy-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]-2-methoxy-acetamide,-   [(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]carbamoylmethyl    acetate,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]-2-hydroxy-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfonylphenyl)propan-2-yl]-2-hydroxy-acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]acetamide,-   N-[(1R,2S)-1-(4-ethylsulfanylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-(4-cyclopropylsulfanylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-hydroxy-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]cyclopropanecarboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]cyclopropanecarboxamide,-   N-[(1R,2S)-1-(2,5-dioxabicyclo[4.4.0]deca-7,9,11-trien-8-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-naphthalen-2-yl-propan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-naphthalen-2-yl-propan-2-yl]-2-hydroxy-acetamide,-   N-[(1R,2S)-1-(3-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-(3-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-hydroxy-acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methylphenyl)propan-2-yl]acetamide,-   N-[(1R,2S)-1-[4-(ethylsulfanylmethyl)phenyl]-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-[4-(ethylsulfinylmethyl)phenyl]-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-[4-(ethylsulfanylmethyl)phenyl]-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-hydroxy-acetamide,-   4-amino-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]butanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-3-methoxy-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-methoxy-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]benzamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-phenyl-acetamide,-   [(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]carbamoylmethyl    acetate,-   methyl[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]carbamoylformate,-   [(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]carbamoylformic    acid,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-methyl-propanamide,-   2-chloro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   2,2-dichloro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   2,2,2-trichloro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]butanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]cyclobutanecarboxamide,-   2,2-difluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   2-fluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   2-chloro-2-fluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   (2S)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-hydroxy-propanamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-hydroxyphenyl)propan-2-yl]acetamide,-   N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-fluoro-acetamide,-   N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide,-   N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   2-fluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-methoxy-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-methyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]cyclopentanecarboxamide,-   (2R)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-hydroxy-propanamide,-   (2S)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-hydroxy-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-[4-(trifluoromethyl)phenyl]propan-2-yl]-2-methoxy-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-[4-(trifluoromethyl)phenyl]propan-2-yl]-2-hydroxy-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-[4-(trifluoromethyl)phenyl]propan-2-yl]propanamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-hydroxy-acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-hydroxy-acetamide,-   2,2,2-trifluoro-N-[(2S,3S)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenoxy-butan-2-yl]acetamide,-   2,2,2-trifluoro-N-[(2R,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenoxy-butan-2-yl]acetamide,-   2,2,2-trifluoro-N-[(2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenoxy-butan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-(2-methoxyethoxy)acetamide,-   2,2,2-trifluoro-N-[(2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-yl]acetamide,-   N-[(2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-yl]-2,2-dimethyl-propanamide,-   N-[(2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-yl]-2-hydroxy-acetamide,-   tert-butyl[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]carbamoylformate,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]oxamide,-   propan-2-yl[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]carbamoylformate,-   ethyl[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]carbamoylformate,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-N-methyl-oxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-N′,N′-dimethyl-oxamide,-   N′-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-N-propan-2-yl-oxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-N′-tert-butyl-oxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-4-(trifluoromethyl)benzamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]1,3-oxazole-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]1,3-oxazole-4-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]furan-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]thiophene-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]pyrimidine-4-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]pyridine-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxyphenyl)propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-pentan-2-yl]-2-hydroxy-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-pentan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)pentan-2-yl]-2-hydroxy-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)pentan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-butan-2-yl]-2-hydroxy-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-butan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)butan-2-yl]-2-hydroxy-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)butan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2R)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-yl]acetamide,-   N-[(1R,2S)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-yl]acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]sulfanyl-1-phenyl-propan-2-yl]acetamide,-   1-(Cyclopentyl)-3-{(1S,2R)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl)oxy]-1-methyl-2-phenyl-ethyl}urea,-   1-{(1S,2R)-2-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-1-methyl-2-phenylethyl}-3-(2-furylmethyl)urea,-   Ethyl    N-{[(1S,2R)-2-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-methyl-2-phenylethyl]carbamoyl}glycinate,-   1-((R)-1,2-Dimethylpropyl)-3-{(1S,2R)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-1-methyl-2-phenylethyl}urea,-   1-{(1S,2R)-2-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-1-methyl-2-phenylethyl}-3-(2-furylmethyl)thiourea,-   N-{(1S)-1-[(R)-(3-Fluorophenyl)-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}methyl}-3-methyl-butyl}-2-methoxyacetamide,-   2,2,2-Trifluoro-N-{(1S)-1-[(R)-(3-Fluorophenyl)-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}methyl}-3-methylbutyl}-acetamide,-   N-[(1S)-(2R)-(3-Fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-(methoxymethyl)ethyl]-2-methoxyacetamide,-   N-[(1S)-(2R)-(3-Fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(methoxymethyl)ethyl]furan-2-carboxamide,-   N-[(1S)-2-(3-Fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(hydroxymethyl)ethyl]-2-methoxyacetamide,-   N-[(1S,2R)-1-Methyl-2-phenyl-2-{[1-(3-pyridyl)-1H-indazol-5-yl]oxy}ethyl]furan-2-carboxamide,-   N-[(1S,2R)-1-Methyl-2-phenyl-2-{[1-(4-pyridyl)-1H-indazol-5-yl]oxy}ethyl]furan-2-carboxamide,-   Methyl    4-(5-{(1R,2S)-2-[(2-furylcarbonyl)amino]-1-phenylpropoxy}-1H-indazol-1-yl)benzoate,-   N-{(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenylpropan-2-yl}-5-methyl-[1,3,4]oxadiazol-2-carboxamide,-   2-methoxy-N-[(1R,2S)-1-phenyl-1-(1-pyridin-2-ylindazol-5-yl)oxy-propan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-(6-chloropyridazin-3-yl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2,2,2-trifluoro-acetamide,-   2-methoxy-N-[(1R,2S)-1-phenyl-1-(1-pyrimidin-2-ylindazol-5-yl)oxy-propan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-hydroxy-acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-quinolin-3-yl-propan-2-yl]acetamide,-   N-[(1R,2S)-1-(2,5-dioxabicyclo[4.4.0]deca-7,9,11-trien-8-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-hydroxy-acetamide,-   N-[(1R,2S)-1-(2,5-dioxabicyclo[4.4.0]deca-7,9,11-trien-8-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   (2S)-N-[(1R,2S)-1-(2,5-dioxabicyclo[4.4.0]deca-7,9,11-trien-8-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]pyrrolidine-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-chlorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-(2,5-dioxabicyclo[4.4.0]deca-7,9,11-trien-8-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-difluoro-propanamide,-   N-[(1R,2S)-1-[1-(4-chlorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2,2-difluoro-propanamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-phenyl-1-(1-propan-2-ylindazol-5-yl)oxy-propan-2-yl]acetamide,-   N-[(1R,2S)-1-(1-cyclopentylindazol-5-yl)oxy-1-phenyl-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-thiophene-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-3-methyl-thiophene-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1-methyl-pyrrole-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]thiophene-3-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-1,2-oxazole-3-carboxamide,-   N-[2-[1-(4-fluorophenyl)indazol-5-yl]oxy-2-phenyl-acetyl]-2-methyl-propanamide,-   (2R)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-[4-(trifluoromethyl)phenyl]propan-2-yl]-2-hydroxy-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-[4-(trifluoromethyl)phenyl]propan-2-yl]-1-hydroxy-cyclopropane-1-carboxamide,-   (2S)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-[4-(trifluoromethyl)phenyl]propan-2-yl]-2-hydroxy-propanamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-[4-(hydroxymethyl)phenyl]indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-[4-(morpholin-4-ylmethyl)phenyl]indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-[4-(dimethylaminomethyl)phenyl]indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2,2,2-trifluoro-acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-[3-(hydroxymethyl)phenyl]indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-[3-(morpholin-4-ylmethyl)phenyl]indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-[3-(dimethylaminomethyl)phenyl]indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2,2,2-trifluoro-acetamide,-   2,2-dimethyl-N-[2,2,2-trifluoro-1-[[1-(4-fluorophenyl)indazol-5-yl]oxy-phenyl-methyl]ethyl]propanamide,-   N-[(1S,2R)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]cyclopropanecarboxamide,-   N-[(1R,2S)-1-(3,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide,-   N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-(2,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-(5-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-(5-fluoro-2-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxy-3,5-dimethyl-phenyl)propan-2-yl]acetamide,-   N-[(1R,2S)-1-(4-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-(3-chloro-5-fluoro-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2,4,5-trimethylphenyl)propan-2-yl]acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-tert-butylphenyl)propan-2-yl]acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2-methoxyphenyl)propan-2-yl]acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-propylphenyl)propan-2-yl]acetamide,-   N-[(1R,2S)-1-benzo[1,3]dioxol-5-yl-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-(3-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide,-   N-[(1R,2S)-1-(4-chloro-3-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-(4-chloro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-(4-chloro-3-fluoro-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,-   N-[(1R,2S)-1-(3,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(2,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(5-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(5-fluoro-2-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxy-3,5-dimethyl-phenyl)propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(4-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(3-chloro-5-fluoro-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methylphenyl)propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-tert-butylphenyl)propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2-methoxyphenyl)propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-propylphenyl)propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-benzo[1,3]dioxol-5-yl-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(3-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(4-chloro-3-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-methyl-propanamide,-   N-[(1R,2S)-1-(3,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-arboxamide,-   N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-(2,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-arboxamide,-   N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-(5-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-(5-fluoro-2-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxy-3,5-dimethyl-phenyl)propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-(4-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-(3-chloro-5-fluoro-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2,4,5-trimethylphenyl)propan-2-yl]-5-methyl-1,3-thiazole-2-arboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methylphenyl)propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-tert-butylphenyl)propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2-methoxyphenyl)propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-benzo[1,3]dioxol-5-yl-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-(3,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-(2,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-(3    chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1    carboxamide,-   N-[(1R,2S)-1-(5-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxy-3,5-dimethyl-phenyl)propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-(4-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-(3-chloro-5-fluoro-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methylcyclopropane-1-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2,4,5-trimethylphenyl)propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methylphenyl)propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-tert-butylphenyl)propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2-methoxyphenyl)propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-difluoro-propanamide,-   2,2-difluoro-N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]propanamide,-   2,2-difluoro-N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]propanamide,-   2,2-difluoro-N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]propanamide,-   N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-difluoro-propanamide,-   2,2-difluoro-N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]propanamide,-   2,2-difluoro-N-[(1R,2S)-1-(5-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]propanamide,-   2,2-difluoro-N-[(1R,2S)-1-(5-fluoro-2-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]propanamide,-   2,2-difluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxy-3,5-dimethyl-phenyl)propan-2-yl]propanamide,-   N-[(1R,2S)-1-(4-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-difluoro-propanamide,-   N-[(1R,2S)-1-(3-chloro-5-fluoro-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-difluoro-propanamide,-   2,2-difluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methylphenyl)propan-2-yl]propanamide,-   N-[(1R,2S)-1-(3,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-fluoro-2-methyl-propanamide,-   N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-fluoro-2-methyl-propanamide,-   2-fluoro-N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide,-   2-fluoro-N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide,-   N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-fluoro-2-methyl-propanamide,-   N-[(1R,2S)-1-(2,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-fluoro-2-methyl-propanamide,-   2-fluoro-N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide,-   N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-fluoro-2-methyl-propanamide,-   2-fluoro-N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide,-   2-fluoro-N-[(1R,2S)-1-(5-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide,-   2-fluoro-N-[(1R,2S)-1-(5-fluoro-2-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide,-   N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-3-hydroxy-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-3-hydroxy-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-3-hydroxy-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-3-hydroxy-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-3-hydroxy-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-3-hydroxy-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(3,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide,-   N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide,-   N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide,-   N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide,-   N-[(1R,2S)-1-(2,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide,-   N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide,-   N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide,-   2,2,2-trifluoro-N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxy-2-methyl-phenyl)propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-difluoro-propanamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2,4,5-trimethylphenyl)propan-2-yl]-2,2-dimethyl-propanamide,-   N-[(1R,2S)-1-(5-fluoro-2-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide,-   N-[[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]carbamoylmethyl]acetamide,-   2-(carbamoylamino)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]acetamide,-   3-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]imidazolidine-2,4-dione,-   5-bromo-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]thiophene-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methylsulfonyl-thiophene-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide,-   4-cyano-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]thiophene-2-carboxamide,-   5-bromo-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]furan-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-1,3,4-oxadiazole-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1H-imidazole-4-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1H-pyrazole-3-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]1,2-oxazole-3-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1H-1,2,4-triazole-3-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-1H-pyrazole-3-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]1-methyl-imidazole-4-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-1,2-oxazole-4-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1-methyl-triazole-4-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-4,5-dimethyl-furan-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1,5-dimethyl-pyrazole-3-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-1,3-thiazole-4-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-4-methyl-1,3-thiazole-5-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-4-methyl-1,3-thiazole-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-4,5-dimethyl-thiophene-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-3-methoxy-thiophene-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1,9-diazabicyclo[4.3.0]nona-2,4,6,8-tetraene-8-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1H-benzoimidazole-2-arboxamide,-   5-chloro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]thiophene-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]benzothiophene-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]benzothiazole-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-3-hydroxy-5-(trifluoromethyl)thiophene-2-carboxamide,-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-(methoxymethyl)thiophene-2-carboxamide,-   N-[(1R,2S)-1-(2-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide,-   tert-butyl    3-[[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]carbamoyl]pyrrolidine-1-carboxylate,-   2,2-difluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]propanamide,-   (2R)-2-amino-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]propanamide,-   (2R)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]pyrrolidine-2-carboxamide,-   N-[(1S,2S)-3-(2,4-difluorophenoxy)-2-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-methyl-propyl]-2,2,2-trifluoro-acetamide,-   N-[(1S,2R)-2-(2,3-dihydrobenzofuran-6-yl)-2-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-methyl-ethyl]-2,2-difluoro-propanamide,-   N-[(1R,2S)-1-(2,3-dihydrobenzofuran-6-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide,    and-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxy-4-methylsulfanyl-phenyl)propan-2-yl]acetamide,    or a pharmaceutically acceptable salt thereof.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’, ‘definedhereinbefore’ or ‘defined above’ the said group encompasses the firstoccurring and broadest definition as well as each and all of the otherdefinitions for that group.

For the avoidance of doubt it is to be understood that in thisspecification ‘C₁₋₆’ means a carbon group having 1, 2, 3, 4, 5 or 6carbon atoms.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups and may be, butare not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl.The term C₁₋₄ alkyl having 1 to 4 carbon atoms and may be but are notlimited to methyl, ethyl, n-propyl, i-propyl or t-butyl. The term “C₀”in C₀₋₄ alkyl refers to a situation where no carbon atom is present.

The term “alkoxy”, unless stated otherwise, refers to radicals of thegeneral formula —O—R, wherein R is selected from a hydrocarbon radical.The term “alkoxy” may include, but is not limited to methoxy, ethoxy,propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy,allyloxy or propargyloxy.

In this specification, unless stated otherwise, the term “cycloalkyl”refers to an optionally substituted, partially or completely saturatedmonocyclic, bicyclic or bridged hydrocarbon ring system. The term“C₁₋₆cycloalkyl” may be, but is not limited to cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

In this specification, unless stated otherwise, the term“heterocycloalkyl” refers to an optionally substituted, partially orcompletely saturated monocyclic, bicyclic or bridged hydrocarbon ringsystem having one or more heteroatoms independently selected from O, Nor S. The term “C₁₋₆heterocycloalkyl” may be, but is not limited topyrrolidinyl, piperidinyl or tetrahydrofuranyl.

In this specification, unless stated otherwise, the term “A formstogether with Rx a 5 to 6 membered azacyclic ring optionally having oneor more further heteroatoms independently selected from O, N and S”refers to an optionally substituted, aromatic or partially or completelysaturated monocyclic hydrocarbon ring system having one or moreheteroatoms independently selected from O, N or S. This term may be, butis not limited to imidazolidine-2,4-dione.

In this specification, unless stated otherwise, the terms “halo” and“halogen” may be fluorine (fluoro), iodine (iodo), chlorine (chloro) orbromine (bromo).

In this specification, unless stated otherwise, the term “haloalkyl”means an alkyl group as defined above, which is substituted with halo asdefined above. The term “C₁₋₆haloalkyl” may include, but is not limitedto fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl or fluorochloromethyl.

The term “C₁₋₃haloalkylO” or “C₁₋₃haloalkoxy” may include, but is notlimited to fluoromethoxy, difluoromethoxy, trifluoromethoxy,fluoroethoxy or difluoroethoxy.

In this specification, unless stated otherwise, the term “thioalkyl”means an alkyl group as defined above, which is substituted with sulphuratom. The term “C₁₋₆thioalkyl” may include, but is not limited tomethylsulfanyl, ethylsulfanyl or propylsulfanyl.

The term “cycloalkylS” means a sulphur atom substituted with acycloalkyl as defined above such as for instance cyclopropylsulfanyl inexample 15.

The term “C₁₋₄alkylC₁₋₄thioalkyl” or “C₁₋₄alkylSC₁₋₄alkyl” means a alkylgroup with a sulphur atom between the carbon atoms. The term“C₁₋₄alkylC₁₋₄thioalkyl” may include, but is not limited toethylsulfanylmethyl as in example 25.

In this specification, unless stated otherwise, the term “C₅₋₁₀aryl”refers to an aromatic or partial aromatic group having 5 to 10 carbonatoms such as for example, phenyl or naphthyl. In this specification,unless stated otherwise, the term “C₅₋₁₀heteroaryl” refers to a mono- orbicyclic aromatic or partially aromatic ring with 5 to 10 atoms andcontaining one or more heteroatoms independently selected from nitrogen,oxygen or sulphur. Example of heteroaryls are oxazolyl, furyl,thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl,indolyl, indazolyl, benzofuryl, benzothienyl or dioxabicyclodecatrienylas in example 19. Heteroaryl may also be quinolinyl or isoquinolinyl.

When phenyl is substituted by OCH₂O, OCH₂CH₂O or OCH₂CH₂ these groupslink to adjacent carbons on the phenyl ring.

For the avoidance of doubt a group R³ defined as C₅₋₁₀aryl e.g. phenyl,substituted with a group C₁₋₂alkylS(O)_(n) includes a phenyl substitutedwith methylsulphonyl group as in example 12. And a group R⁷ defined asC₅₋₁₀heteroarylC₁₋₃alkyl includes a furylmethyl group as in example 105.

It will be appreciated that throughout the specification, the number andnature of substituents on rings in the compounds of the invention willbe selected so as to avoid sterically undesirable combinations.

One embodiment of the invention relates to compounds of formula Ic

wherein:A is C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀ alkylthio, (C₁₋₁₀ alkyl)(R¹¹)N orC₃₋₇ cycloalkyl, all of which are optionally substituted by halogen,cyano, nitro, hydroxy, thio, C₁₋₆ alkoxy, C₁₋₆ alkylS(O)_(n), R¹²R¹³N,(C₁₋₄ alkyl)C(O)O, C₃₋₇ cycloalkyl, phenyl (itself optionallysubstituted by halogen, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy or OCF₃) orheteroaryl (itself optionally substituted by halogen, C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy or OCF₃); and C₃₋₇ cycloalkyl may additionally be optionallysubstituted by C₁₋₄ alkyl;n is 0, 1 or 2;R¹ and R^(1a) are, independently, hydrogen, C₁₋₄ alkyl or C₁₋₄haloalkyl;R² is hydrogen or C₁₋₄ alkyl;R³ is aryl, (C₁₋₄ alkyl)aryl, (C₁₋₄ alkoxy)aryl, (C₁₋₄ alkylthio)aryl,heteroaryl, (C₁₋₄ alkyl)heteroaryl, (C₁₋₄ alkoxy)heteroaryl or (C₁₋₄alkylthio)heteroaryl [wherein the phenyl rings are optionallysubstituted by halo, C₁₋₆ alkyl (optionally substituted by C₁₋₆alkoxy),C₁₋₆ alkoxy, C₁₋₄ alkylthio, C₃₋₆ cycloalkylthio, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, nitro, cyano, OH, C(O)₂H, C(O)₂(C₁₋₄ alkyl), S(O)₂(C₁₋₄alkyl), S(O)₂(C₃₋₆ cycloalkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),S(O)₂N(C₁₋₄ alkyl)₂, benzyloxy, imidazolyl, C(O)(C₁₋₄ alkyl), C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, NHC(O)(C₁₋₄ alkyl), NR⁵R⁶,OCH₂O, OCH₂CH₂O or OCH₂CH₂; the heteroaryl ring is optionallysubstituted by halo, C₁₋₆alkyl (optionally substituted by C₁₋₆alkoxy),C₁₋₆alkoxy, C₁₋₄ alkylthio, C₃₋₆ cycloalkylthio, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, nitro, cyano, OH, C(O)₂H, C(O)₂(C₁₋₄ alkyl), S(O)₂(C₁₋₄alkyl), S(O)₂(C₃₋₆ cycloalkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),S(O)₂N(C₁₋₄ alkyl)₂, benzyloxy, imidazolyl, C(O)(C₁₋₄ alkyl), C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, NHC(O)(C₁₋₄ alkyl) or NR⁵R⁶];R⁴ is hydrogen, hydroxy, halogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl;W is hydrogen or phenyl, C₃₋₇ cycloalkyl, thienyl, isoxazolyl,pyrazolyl, pyridinyl or pyrimidinyl all of which are optionallysubstituted by halo, C₁₋₆alkyl (optionally substituted by C₁₋₆ alkoxy),C₁₋₆ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, nitro,cyano, OH, C(O)₂H, C(O)₂(C₁₋₄ alkyl), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, benzyloxy, imidazolyl,C(O)(C₁₋₄ alkyl), C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂,NHC(O)(C₁₋₄ alkyl) or NR⁷R⁸;X is CH₂, O, S, S(O), S(O)₂, NH or N(C₁₋₄ alkyl);Y is hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₄ alkylthio, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, nitro, cyano, OH, C(O)₂H, C(O)₂(C₁₋₄ alkyl),S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂,benzyloxy, imidazolyl, C(O)(C₁₋₄ alkyl), C(O)NH₂, C(O)NH(C₁₋₄ alkyl),C(O)N(C₁₋₄ alkyl)₂, NHC(O)(C₁₋₄ alkyl) or NR⁹R¹⁰;R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are, independently, hydrogen, C₁₋₄ alkyl orC₃₋₇ cycloalkyl;R¹¹ is hydrogen or C₁₋₁₀ alkyl;R¹² and R¹³ are, independently, hydrogen or C₁₋₆ alkyl;or a pharmaceutically acceptable salt thereof.

For the avoidance of doubt, the definitions of groups and substituentsfor compounds of formula Ic is as follows and is distinct and separatefrom those for formula I and Ib.

Compounds of formula (Ic) can exist in different isomeric forms (such asenantiomers, diastereomers, geometric isomers or tautomers). The presentinvention covers all such isomers and mixtures thereof in allproportions.

Suitable salts include acid addition salts such as a hydrochloride,hydrobromide, phosphate, acetate, trifluoroacetate, fumarate, maleate,tartrate, citrate, oxalate, methanesulphonate, p-toluenesulphonate,succinate, glutarate or malonate.

The compounds of formula (Ic) may exist as solvates (such as hydrates)and the present invention covers all such solvates.

Alkyl groups and moieties are straight or branched chain and are, forexample, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl ortert-butyl.

Haloalkyl comprises, for example, 1 to 6, such as 1, 2, 3, 4 or 5halogen (such as fluorine or chlorine) atoms. It is, for example, CHF₂,CF₃, CH₂CF₃, C₂F₅ or CH₂Cl. Further examples are CH₂F, CHFCl, CCl₃ orCHCl₂.

Haloalkoxy comprises, for example, 1 to 6, such as 1, 2, 3, 4 or 5halogen (such as fluorine or chlorine) atoms. It is, for example, OCHF₂,OCF₃, OCH₂CF₃, OC₂F₅ or OCH₂Cl.

Cycloalkyl is for example, cyclopropyl, cyclopentyl or cyclohexyl. Itcan also be cyclobutyl.

Aryl is, for example, phenyl or naphthyl. In one aspect of the inventionaryl is phenyl.

Heteroaryl is, for example, a mono-cyclic, aromatic 5- or 6-memberedring containing 1 or 2 nitrogen atoms, said ring being optionally fusedto a benzene ring. Heteroaryl is, for example, pyrrolyl, pyrazolyl,imidazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, benzofuryl orbenzothienyl. Heteroaryl may also be quinolinyl or isoquinolinyl.

When phenyl is substituted by OCH₂O, OCH₂CH₂O or OCH₂CH₂ these groupslink to adjacent carbons on the phenyl ring.

(C₁₋₄ Alkyl)aryl is for example benzyl. (C₁₋₄ Alkoxy)aryl is, forexample, CH₂O-phenyl. (C₁₋₄ Alkylthio)aryl is, for example, CH₂S-phenyl.(C₁₋₄ Alkyl)heteroaryl is, for example, CH₂-pyridinyl.(C₁₋₄Alkoxy)heteroaryl is, for example, CH₂O-pyridinyl. (C₁₋₄Alkylthio)heteroaryl is, for example, CH₂S-pyridinyl.

In one particular aspect the present invention provides a compound offormula (Ic) wherein: A is C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀ alkylthio,(C₁₋₁₀ alkyl)(R¹¹)N or C₃₋₇ cycloalkyl, all of which are optionallysubstituted by halogen, cyano, nitro, hydroxy, thio, C₁₋₆ alkoxy, C₁₋₆alkylS(O)_(n), R¹²R¹³N, C₃₋₇ cycloalkyl, phenyl (itself optionallysubstituted by halogen, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy or OCF₃) orheteroaryl (itself optionally substituted by halogen, C₁₋₄ alkyl, CF₃,C₁₋₄ alkoxy or OCF₃); and C₃₋₇ cycloalkyl may additionally be optionallysubstituted by C₁₋₄ alkyl; n is 0, 1 or 2; R¹ and R^(1a) are,independently, hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; R² is hydrogen orC₁₋₄ alkyl; R³ is phenyl or heteroaryl [wherein phenyl and heteroarylare optionally substituted by halo, C₁₋₆ alkyl (optionally substitutedby C₁₋₆ alkoxy), C₁₋₆ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, nitro, cyano, OH, C(O)₂H, C(O)₂(C₁₋₄ alkyl), S(O)₂(C₁₋₄alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, benzyloxy,imidazolyl, C(O)(C₁₋₄ alkyl), C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄alkyl)₂, NHC(O)(C₁₋₄ alkyl) or NR⁵R⁶; and phenyl may additionally beoptionally substituted on adjacent carbons by OCH₂O, OCH₂CH₂O orOCH₂CH₂]; R⁴ is hydrogen, hydroxy, halogen, C₁₋₄ alkyl or C₁₋₄haloalkyl; W is hydrogen, phenyl, C₃₋₇ cycloalkyl, thienyl, isoxazolyl,pyrazolyl, pyridinyl or pyrimidinyl all of which are optionallysubstituted by halo, C₁₋₆alkyl (optionally substituted by C₁₋₆ alkoxy),C₁₋₆ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, nitro,cyano, OH, C(O)₂H, C(O)₂(C₁₋₄ alkyl), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, benzyloxy, imidazolyl,C(O)(C₁₋₄ alkyl), C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂,NHC(O)(C₁₋₄ alkyl) or NR⁷R⁸; X is CH₂, O, S, S(O), S(O)₂, NH or N(C₁₋₄alkyl); Y is hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₄ alkylthio, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, nitro, cyano, OH, C(O)₂H, C(O)₂(C₁₋₄ alkyl),S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂,benzyloxy, imidazolyl, C(O)(C₁₋₄ alkyl), C(O)NH₂, C(O)NH(C₁₋₄ alkyl),C(O)N(C₁₋₄ alkyl)₂, NHC(O)(C₁₋₄ alkyl) or NR⁹R¹⁰; R⁵, R⁶, R⁷, R⁸, R⁹ andR¹⁰ are, independently, hydrogen, C₁₋₄ alkyl or C₃₋₇ cycloalkyl; R¹¹ ishydrogen or C₁₋₁₀ alkyl; R¹² and R¹³ are, independently, hydrogen orC₁₋₆ alkyl; or a pharmaceutically acceptable salt thereof.

In a further aspect the present invention provides a compound of formula(Ic) wherein A is C₃₋₇ cycloalkyl (optionally substituted by halogen orC₁₋₆ alkyl), C₁₋₄ alkyl (such as ethyl or tert-butyl), C₁₋₄ haloalkyl(such as CF₃), C₁₋₄ alkoxy (such as methoxy) C₁₋₄ hydroxyalkyl (such asHOCH₂, HO(CH₃)CH or HO(CH₃)₂C), C₁₋₄ alkoxy(C₁₋₄ alkyl) (such asCH₃OCH₂) or C₁₋₄ alkylC(O)O(C₁₋₄ alkyl) (such as CH₃C(O)OCH₂).

In another aspect the present invention provides a compound of formula(Ic) wherein A is C₃₋₇ cycloalkyl (optionally substituted by halogen orC₁₋₆ alkyl).

In a further aspect the present invention provides a compound of formula(Ic) wherein A is C₁₋₄ alkyl (such as ethyl), C₁₋₄ haloalkyl (such asCF₃) or C₁₋₄ alkoxy (such as methoxy).

In another aspect the present invention provides a compound of formula(Ic) wherein R¹ is C₁₋₄ alkyl (for example methyl).

In yet another aspect the present invention provides a compound offormula (Ic) wherein R^(1a) is hydrogen.

In a further aspect the present invention provides a compound of formula(Ic) wherein R² is hydrogen.

In a still further aspect the present invention provides a compound offormula (Ic) wherein R³ is phenyl optionally substituted by halo, C₁₋₆alkyl (optionally substituted by C₁₋₆ alkoxy), C₁₋₆alkoxy, C₁₋₄alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, nitro, cyano, OH, C(O)₂H,C(O)₂(C₁₋₄ alkyl), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),S(O)₂N(C₁₋₄ alkyl)₂, benzyloxy, imidazolyl, C(O)(C₁₋₄ alkyl), C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, NHC(O)(C₁₋₄ alkyl) or NR⁵R⁶;wherein R⁵ and R⁶ are, independently, hydrogen, C₁₋₄ alkyl or C₃₋₇cycloalkyl.

In a further aspect the present invention provides a compound of formula(Ic) wherein R³ is phenyl optionally substituted by halo, C₁₋₆ alkyl(such as ethyl), C₁₋₆ alkoxy (such as methoxy), C₁₋₄ alkylthio (such asCH₃S or C₂H₅S), C₃₋₆ cycloalkylthio (such as cyclopropylthio), C₁₋₄haloalkyl (such as CF₃) or S(O)₂(C₁₋₄ alkyl) (such as S(O)₂CH₃).

In a still further aspect the present invention provides a compound offormula (Ic) wherein Y is hydrogen.

In another aspect the present invention provides a compound of formula(Ic) wherein R⁴ is hydrogen.

In yet another aspect the present invention provides a compound offormula (Ic) wherein W is phenyl optionally substituted by halo, C₁₋₆alkyl (optionally substituted by C₁₋₆ alkoxy), C₁₋₆ alkoxy, C₁₋₄alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, nitro, cyano, OH, C(O)₂H,C(O)₂(C₁₋₄ alkyl), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),S(O)₂N(C₁₋₄ alkyl)₂, benzyloxy, imidazolyl, C(O)(C₁₋₄ alkyl), C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, NHC(O)(C₁₋₄ alkyl) or NR⁷R⁸;wherein R⁷ and R⁸ are, independently, hydrogen, C₁₋₄ alkyl or C₃₋₇cycloalkyl.

In another aspect the present invention provides a compound of formula(Ic) wherein W is phenyl optionally substituted by halo (such asfluoro), C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₄ haloalkyl or C₁₋₄ haloalkoxy.

In a further aspect the present invention provides a compound of formula(Ic) wherein X is O, S, S(O) or S(O)₂.

In a still further aspect the present invention provides a compound offormula (Ic) wherein X is O.

In a further aspect the present invention provides a compound of formula(Ic) wherein A is C₃₋₇ cycloalkyl (optionally substituted by halogen orC₁₋₆ alkyl), C₁₋₄ alkyl (such as ethyl or tert-butyl), C₁₋₄ haloalkyl(such as CF₃), C₁₋₄ alkoxy (such as methoxy) C₁₋₄ hydroxyalkyl (such asHOCH₂, HO(CH₃)CH or HO(CH₃)₂C), C₁₋₄ alkoxy(C₁₋₄ alkyl) (such asCH₃OCH₂) or C₁₋₄ alkylC(O)O(C₁₋₄ alkyl) (such as CH₃C(O)OCH₂); R¹ isC₁₋₄ alkyl (for example methyl); R^(1a) is hydrogen; R² is hydrogen; R³is phenyl optionally substituted by halo, C₁₋₆alkyl (such as ethyl),C₁₋₆ alkoxy (such as methoxy), C₁₋₄ alkylthio (such as CH₃S or C₂H₅S),C₃₋₆ cycloalkylthio (such as cyclopropylthio), C₁₋₄ haloalkyl (such asCF₃) or S(O)₂(C₁₋₄ alkyl) (such as S(O)₂CH₃); Y is hydrogen; R⁴ ishydrogen; W is phenyl optionally substituted by halo (such as fluoro),C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₄ haloalkyl or C₁₋₄ haloalkoxy; and X is O.

In a further aspect the present invention provides a compound of formula(Ic) having the stereochemistry shown in the structure immediatelybelow:

In another aspect the present invention provides the individualcompound:

-   N-((1S,2R)-2-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl)cyclopropanecarboxamide;-   2,2,2-Trifluoro-N-((1S,2R)-2-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl)acetamide;-   N-((1S,2R)-2-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl)propanamide;-   Methyl    ((1S,2R)-2-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl)carbamate;-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-hydroxy-2-methyl-propanamide;-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]acetamide;-   N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-hydroxy-acetamide;-   N-{2-[1-(4-Fluoro-phenyl)-1H-indazo-5-yloxy]-2-(3-methoxy-phenyl)-1-methyl-ethyl}-2,2-dimethyl-propionamide;-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]-2-methoxy-acetamide;-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]carbamoylmethyl    acetate;-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]-2-hydroxy-acetamide;-   N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfonylphenyl)propan-2-yl]-2-hydroxy-acetamide;-   2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]acetamide;-   N-[(1R,2S)-1-(4-Ethylsulfanylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide;    or,-   N-[(1R,2S)-1-(4-cyclopropylsulfanylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide;    or a pharmaceutically acceptable salt thereof.

Compounds of the present invention have been named with the aid ofcomputer software (ACDLabs 8.0/Name(IUPAC)).

Compounds of formula (I), (Ib) or (Ic) may include an asymmetric centreand be chiral in nature. Where the compound is chiral, it may be in theform of a single stereoisomer, such as a enantiomer, or it may be in theform of mixtures of these stereoisomers in any proportions, includingracemic mixtures. Therefore, all enantiomers, diastereomers, racematesand mixtures thereof are included within the scope of the invention. Thevarious optical isomers may be isolated by separation of a racemicmixture of the compounds using conventional techniques, for example,fractional crystallisation, or HPLC. Alternatively the optical isomersmay be obtained by asymmetric synthesis, or by synthesis from opticallyactive starting materials.

Compounds of formula (I), (Ib) or (Ic) above may be converted to apharmaceutically acceptable salt thereof, preferably an acid additionsalt such as a hydrochloride, hydrobromide, phosphate, sulphate,acetate, ascorbate, benzoate, fumarate, hemifumarate, furoate,succinate, maleate, tartrate, citrate, oxalate, xinafoate,methanesulphonate, p-toluenesulphonate, benzenesulphonate,ethanesulphonate, 2-naphthalenesulfonate, mesytilenesulfonate, nitricacid, 1,5-naphthalene-disulphonate, p-xylenesulphonate, aspartate orglutamate.

They may also include basic addition salts such as an alkali metal saltfor example sodium or potassium salts, an alkaline earth metal salt forexample calcium or magnesium salts, a transition metal salt such as azinc salt, an organic amine salt for example a salt of triethylamine,diethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine,piperazine, procaine, dibenzylamine, N,N-dibenzylethylamine, choline or2-aminoethanol or amino acids for example lysine or arginine.

The compounds of formula (I), (Ib) or (Ic) and pharmaceuticallyacceptable salts thereof may exist in solvated, for example hydrated, aswell as unsolvated forms, or as cocrystals and the present inventionencompasses all such forms.

Process

The compounds of formula (I) can be prepared using or adapting methodsdisclosed in the art, or by using or adapting the method disclosed inthe Example below. Starting materials for the preparative methods areeither commercially available or can be prepared by using or adaptingliterature methods.

One embodiment relates to a process for the preparation of compounds offormula (I) by coupling a compound of formula (II):

with acylation reagents of formula (IIIa) or formula (IIIb)

wherein R¹, R^(1a), R², R³, R⁴, R⁷, A, W, X, Y and Z are defined as incompounds of formula (I), and L¹ is a leaving group (such as halogen(for example chloro) or, when L¹═OH, a leaving group generated byreaction of a coupling reagent (such as HATU with a carboxylic acid).The reaction may be performed in a suitable solvent (such as pyridine,THF or DMF), in the presence of a suitable base (such as a tri(C₁₋₆alkyl)amine, for example diisopropylethylamine, or pyridine) and at asuitable temperature (such as −10° to 50° C.).

Another embodiment relates to a process for the preparation of compoundsof formula (II) according to steps a, b or c.

a) A compound of formula (II), wherein X is O, S or NH, may be preparedby coupling a compound of formula (IV)

wherein R⁴, W and Y are defined as in compounds of formula (I) and L² isa leaving group (such as halogen or triflate) with a compound of formula(V)

wherein R¹, R^(1a), R² and R³ are defined as in compounds of formula (I)and G corresponds to R³ or a protected precurser to R³.

The reaction can be performed in a suitable solvent (such as an aromaticsolvent, for example toluene) or a polar, aprotic solvent, such as DMFor butyronitril, in the presence of a suitable base (such as a alkalimetal alkoxide (for example sodium tert-butoxide) or, cesium carbonate,preferable mediated by a suitable metal catalyst such as Copper(I)iodide at a suitable temperature (for example in the range 80° to 120°C.).

Or,

b) A compound of formula (II) may be prepared by reacting a compound offormula (VII)

with a compound of formula (VIII)

wherein R¹, R², R⁴, R³, X, W and Y are defined as in compounds offormula (I), G corresponds to R³ or a protected precurser to R³ and L³is a leaving group (such as halogen, mesylate or tosylate).

The reaction can be performed in a suitable solvent (such as DCM, DMF oracetonitrile), in the presence of a suitable base (such as an alkalimetal carbonate, for example cesium carbonate or potassium carbonate) ata suitable temperature (for example in the range −10 to 50° C.),followed by a subsequent reductive amination step using or adoptingliterature methods.

Or,

c) a compound of formula (II) may be prepared by reacting a compound offormula (VIII) with a compound of formula (IX)

wherein R¹, R^(1a), R² and R³ are defined as in compounds of formula (I)and PG is a suitable protecting group such as BOC, Ms, Ns, Ts or relatedcarbonyl- or sulfonyl residues.

The reaction can be performed in a suitable solvent such as DCM ortoluene in the presence of a suitable base such as NaH or KOtBu,followed by a deprotection step using or adopting literature methods.

As a specific case of a compound of formula (V), a compound of formula(X) might be used to prepare a compound of formula (II)

wherein R¹, R^(1a) and G are defined as in compounds of formula (V).

Compounds of formula (X) may be prepared by reacting a nucleophile G-Mwith a carbonyl compound of formula (XI) followed reduction andsubsequent deprotection of the intermediate of formula (XII)

wherein R¹, R^(1a) and R³ are defined as in compounds of formula (I) andG corresponds to R³ or a protected precurser to R³ and L is a leavinggroup (such as alkoxy, methoxy(methyl)amino). M is a metal such as L¹ orMg-halide.

The addition of the nucleophile may be performed in a suitable aproticsolvent such as THF at moderate temperature between −10 and 50° C. Thefollowing reduction and deprotection steps might be carried out by usingor adopting literature methods.

Alternatively, compounds of formula (X) may be prepared by a reaction ofa nuceophile G-M with an aldehyde of formula (XIII) and a subsequentdeprotection.

wherein R¹, R^(1a) and R³ are defined as in compounds of formula (I) andG corresponds to R³ or a protected precurser to R³ and PG is aprotecting group or hydrogen. M is a metal such as an alkali metal (e.g.Li) or Mg-halide.

The reaction may be performed by following disclosed protocols foraddition of carbanions to aldehydes.

Another way to prepare a compound of formula (X) is the reaction ofnitroalkyles of formula (XIV) with aldehydes of formula (XV), followedby reduction of the nitro function

wherein R¹ and R^(1a) and R³ are defined as in compounds of formula (I),G corresponds to R³ or a protected precurser to R³ and PG is aprotecting group or hydrogen.

Both steps may be carried out by following or adopting literaturemethods.

Medical Use

Because of their ability to bind to the glucocorticoid receptor thecompounds of formula (I), (Ib) or (Ic) are useful as anti-inflammatoryagents, and can also display antiallergic, immunosuppressive andanti-proliferative actions. Thus, a compound of formula (I), (Ib) or(Ic), or a pharmaceutically acceptable salt thereof can be used as amedicament for the treatment or prophylaxis of one or more of thefollowing pathologic conditions (disease states) in a mammal (such as ahuman):

(i) Lung diseases, which coincide with inflammatory, allergic and/orproliferative processes: chronically obstructive lung diseases of anyorigin, mainly bronchial asthma, chronic obstructive pulmonary disease

bronchitis of different origins

Adult respiratory distress syndrome (ARDS), acute respiratory distresssyndrome

Bronchiectases

all forms of restructive lung diseases, mainly allergic alveolitis

all forms of pulmonary edema, mainly toxic pulmonary edema

sarcoidoses and granulomatoses, such as Boeck's disease

(ii) Rheumatic diseases/auto-immune diseases/degenerative jointdiseases, which coincide with inflammatory, allergic and/orproliferative processes:

all forms of rheumatic diseases, especially rheumatoid arthritis, acuterheumatic fever, polymyalgia rheumatica, collagenoses, Behçet's disease

reactive arthritis

inflammatory soft-tissue diseases of other origins

arthritic symptoms in degenerative joint diseases (arthroses)

traumatic arthritides

collagen diseases of other origins, for example systemic lupuserythematodes, discoid lupus erythematosus, sclerodermia, polymyositis,dermatomyositis, polyarteritis nodosa, temporal arteritis

Sjögren's syndrome, Still syndrome, Felty's syndrome

Vitiligo

Soft-tissue rheumatism

(iii) Allergies, which coincide with inflammatory, allergic and/orproliferative processes:

All forms of allergic reactions, for example Quincke's edema, insectbites, allergic reactions to pharmaceutical agents, blood derivatives,contrast media, etc., anaphylactic shock, urticaria, contact dermatitis(e.g. allergic and irritative), allergic vascular diseasesAllergic vasculitisinflammatory vasculitis(iv) Vascular inflammations (vasculitides)Panarteritis nodosa, temporal arteritis, erythema nodosumPolyarteris nodosaWegner's granulomatosisGiant-cell arteritis(v) Dermatological diseases, which coincide with inflammatory, allergicand/or proliferative processes:atopic dermatitis (mainly in children)exfoliative dermatitis,psoriasiserythematous diseases, triggered by different noxae, for exampleradiation, chemicals, burns, etc.acid burnsbullous dermatoses, such as, for example, autoimmune pemphigus vulgaris,bullous pemphigoiddiseases of the lichenoid groupitching (for example of allergic origins)all forms of eczema, such as, for example, atopic eczema or seborrhealeczema rosaceapemphigus vulgariseiythema exudativum multiformeerythema nodosumbalanitisPruritis, such as, for example, allergic origin)Manifestation of vascular diseasesvulvitisinflammatory hair loss, such as alopecia areatacutaneous T-cell lymphomaRashes of any origin or dermatosesPsoriasis and parapsoriasis groupsPityriasis rubra pilaris(vi) Nephropathies, which coincide with inflammatory, allergic and/orproliferative processes:nephrotic syndromeall nephritides, such as, for example, glomerulonephritis(vii) Liver diseases, which coincide with inflammatory, allergic and/orproliferative processes:acute liver cell decompositionacute hepatitis of different origins, for example virally-, toxically-or pharmaceutical agent-inducedchronically aggressive and/or chronically intermittent hepatitis(viii) Gastrointestinal diseases, which coincide with inflammatory,allergic and/or proliferative processes:regional enteritis (Crohn's disease)GastritisReflux esophagitisulcerative colitisgastroenteritis of other origins, for example native sprue(ix) Proctological diseases, which coincide with inflammatory, allergicand/or proliferative processes:anal eczemafissureshaemorrhoidsidiopathic proctitis(x) Eye diseases, which coincide with inflammatory, allergic and/orproliferative processes:allergic keratitis, uvenitis iritisconjunctivitisblepharitisoptic neuritischorioiditissympathetic ophthalmia(xi) Diseases of the ear-nose-throat area, which coincide withinflammatory, allergic and/or proliferative processes:allergic rhinitis, hay feverotitis extema, for example caused by contact dermatitis, infection, etc.otitis media(xii) Neurological diseases, which coincide with inflammatory, allergicand/or proliferative processes:cerebral edema, mainly tumor-induced cerebral edemamultiple sclerosisacute encephalomyelitisdifferent forms of convulsions, for example infantile nodding spasmsMeningitisspinal cord injuryStroke(xiii) Blood diseases, which coincide with inflammatory, allergic and/orproliferative processes:acquired haemolytic anemiathrombocytopenia such as for example idiopathic thrombocytopeniaM. Hodgkins or Non-Hodgkins lymphomas,thrombocythemias,erythrocytoses(xiv) Tumor diseases, which coincide with inflammatory, allergic and/orproliferative processes:acute lymphatic leukaemiamalignant lymphomalymphogranulomatoseslymphosarcomaextensive metastases, mainly in breast and prostate cancers(xv) Endocrine diseases, which coincide with inflammatory, allergicand/or proliferative processes:endocrine orbitopathythyrotoxic crisisde Quervain's thyroiditisHashimoto's thyroiditisHyperthyroidismBasedow's diseaseGranulomatous thyroiditisLymphadenoid goiter(xvi) Transplants, which coincide with inflammatory, allergic and/orproliferative processes;(xvii) Severe shock conditions, which coincide with inflammatory,allergic and/orproliferative processes, for example anaphylactic shock(xviii) Substitution therapy, which coincides with inflammatory,allergic and/orproliferative processes, with:innate primary suprarenal insufficiency, for example congenitaladrenogenital syndrome acquired primary suprarenal insufficiency, forexample Addison's disease, autoimmune adrenalitis, meta-infective,tumors, metastases, etc.innate secondary suprarenal insufficiency, for example congenitalhypopituitarism acquired secondary suprarenal insufficiency, for examplemeta-infective, tumors, etc.(xix) Emesis, which coincides with inflammatory, allergic and/orproliferative processes:for example in combination with a 5-HT₃-antagonist incytostatic-agent-induced vomiting.(xx) Pains of inflammatory origins, e.g., lumbago

Without prejudice to the foregoing, the compounds of formula (I), (Ib)or (Ic) can also be used to treat disorders such as: diabetes type I(insulin-dependent diabetes), Guillain-Barrésyndrome, restenoses afterpercutaneous transluminal angioplasty, Alzheimer's disease, acute andchronic pain, arteriosclerosis, reperfusion injury, thermal injury,multiple organ injury secondary to trauma, acute purulent meningitis,necrotizing enterocolitis and syndromes associated with hemodialysis,leukopheresis, granulocyte transfusion, Conies Syndrome, primary andsecondary hyperaldosteronism, increased sodium retention, increasedmagnesium and potassium excretion (diuresis), increased water retention,hypertension (isolated systolic and combined systolic/diastolic),arrhythmias, myocardial fibrosis, myocardial infarction, Bartter'sSyndrome, disorders associated with excess catecholamine levels,diastolic and systolic congestive heart failure (CHF), peripheralvascular disease, diabetic nephropathy, cirrhosis with edema andascites, oesophageal varicies, muscle weakness, increased melaninpigmentation of the skin, weight loss, hypotension, hypoglycemia,Cushing's Syndrome, obesity, glucose intolerance, hyperglycemia,diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation,autoimmune disorders, tissue rejection associated with organ transplant,malignancies such as leukemias and lymphomas, rheumatic fever,granulomatous polyarteritis, inhibition of myeloid cell lines, immuneproliferation/apoptosis, HPA axis suppression and regulation,hypercortisolemia, modulation of the Th1/Th2 cytokine balance, chronickidney disease, hypercalcemia, acute adrenal insufficiency, chronicprimary adrenal insufficiency, secondary adrenal insufficiency,congenital adrenal hyperplasia, Little's syndrome, systemicinflammation, inflammatory bowel disease, Wegener's granulomatosis,giant cell arthritis, osteoarthritis, angioneurotic edema, tendonitis,bursitis, autoimmune chronic active hepatitis, hepatitis, cinhosis,panniculitis, inflamed cysts, pyoderma gangrenosum, eosinophilicfasciitis, relapsing polychondritis, sarcoidosis Sweet's disease, type 1reactive leprosy, capillary hemangiomas, lichen planus, erythema nodosumacne, hirsutism, toxic epidermal necrolysis, erythema multiform,psychoses, cognitive disorders (such as memory disturbances) mooddisorders (such as depression and bipolar disorder), anxiety disordersand personality disorders.

As used herein the term “congestive heart failure” (CHF) or “congestiveheart disease” refers to a disease state of the cardiovascular systemwhereby the heart is unable to efficiently pump an adequate volume ofblood to meet the requirements of the body's tissues and organ systems.Typically, CHF is characterized by left ventricular failure (systolicdysfunction) and fluid accumulation in the lungs, with the underlyingcause being attributed to one or more heart or cardiovascular diseasestates including coronary artery disease, myocardial infarction,hypertension, diabetes, valvular heart disease, and cardiomyopathy. Theterm “diastolic congestive heart failure” refers to a state of CHFcharacterized by impairment in the ability of the heart to properlyrelax and fill with blood. Conversely, the term “systolic congestiveheart failure” refers to a state of CHF characterized by impairment inthe ability of the heart to properly contract and eject blood.

As will be appreciated by one of skill in the art, physiologicaldisorders may present as a “chronic” condition, or an “acute” episode.The term “chronic”, as used herein, means a condition of slow progressand long continuance. As such, a chronic condition is treated when it isdiagnosed and treatment continued throughout the course of the disease.Conversely, the term “acute” means an exacerbated event or attack, ofshort course, followed by a period of remission. Thus, the treatment ofphysiological disorders contemplates both acute events and chronicconditions. In an acute event, compound is administered at the onset ofsymptoms and discontinued when the symptoms disappear.

In another aspect the present invention provides the compounds orformula (I), (Ib) or (Ic), or a pharmaceutically acceptable saltthereof, for use in therapy (such as a therapy described above).

In yet another aspect the present invention provides the use of acompound of formula (I), (Ib) or (Ic), or a pharmaceutically acceptablesalt thereof, in the manufacture of a medicament for use in thetreatment of a glucocorticoid receptor mediated disease state (such as adisease state described above).

In a further aspect the invention provides the use of a compound offormula (I), (Ib) or (Ic), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for use in the treatment ofan inflammatory condition (such as an arthritic).

In a still further aspect the invention provides the use of a compoundof formula (I), (Ib) or (Ic), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for use in the treatment ofasthma.

In another aspect the invention provides the use of a compound offormula (I), (Ib) or (Ic), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for use in the treatment ofCOPD.

In another aspect the present invention provides the compounds orformula (I), (Ib) or (Ic), or a pharmaceutically acceptable saltthereof, for use in treating an inflammatory condition, asthma and/orCOPD.

The present invention further provides a method of treating aglucocorticoid receptor mediated disease state (such as a disease statedescribed above), an inflammatory condition, asthma and/or COPD, in amammal (such as man), which comprises administering to a mammal in needof such treatment an effective amount of a compound of formula (I), (Ib)or (Ic), or a pharmaceutically acceptable salt thereof.

In the context of the present specification, the term “therapy” and“treatment” also includes prophylaxis and prevention unless there arespecific indications to the contrary. The terms “therapeutic” and“therapeutically” should be construed accordingly.

In this specification, unless stated otherwise, the terms “inhibitor”and “antagonist” mean a compound that by any means, partly orcompletely, blocks the transduction pathway leading to the production ofa response by the agonist. An agonist may be a full or partial agonist.

The term “disorder”, unless stated otherwise, means any condition anddisease associated with glucocorticoid receptor activity.

Pharmaceutical Composition

In order to use a compound of formula (I), (Ib) or (Ic), or apharmaceutically acceptable salt thereof, for the therapeutic treatmentof a mammal, said active ingredient is normally formulated in accordancewith standard pharmaceutical practice as a pharmaceutical composition.

Therefore another aspect the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I), (Ib) or (Ic), or apharmaceutically acceptable salt thereof, (active ingredient) and apharmaceutically acceptable adjuvant, diluent or carrier. One embodimentrelates to the use of a pharmaceutical composition comprising a compoundof formula (I), (Ib) or (Ic), or a pharmaceutically acceptable saltthereof, for treating a glucocorticoid receptor mediated disease state(such as a disease state described above), an inflammatory condition,asthma and/or COPD.

A further aspect the present invention provides a process for thepreparation of said composition comprising mixing the active ingredientwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositioncan comprise from 0.05 to 99% w (percent by weight), for example from0.05 to 80% w, such as from 0.10 to 70% w (for example from 0.10 to 50%w), of active ingredient, all percentages by weight being based on totalcomposition.

A pharmaceutical composition of the present invention can beadministered in a standard manner for the disease condition that it isdesired to treat, for example by topical (such as to the lung and/orairways or to the skin), oral, rectal or parenteral administration.Thus, a compound of formula (I), (Ib) or (Ic), or a pharmaceuticallyacceptable salt thereof, may be formulated into the form of, forexample, an aerosol, a powder (for example dry or dispersible), atablet, a capsule, a syrup, a granule, an aqueous or oily solution orsuspension, an (lipid) emulsion, a suppository, an ointment, a cream,drops, or a sterile injectable aqueous or oily solution or suspension.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule containing between 0.1 mg and 10 g of active ingredient.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous, intraarticular or intramuscularinjection.

In one embodiment the compounds of formula (I), (Ib) or (Ic), or apharmaceutically acceptable salt thereof, are administered orally.

In another embodiment the compounds of formula (I), (Ib) or (Ic), or apharmaceutically acceptable salt thereof, are administered byinhalation.

Buffers, pharmaceutically-acceptable cosolvents such as polyethyleneglycol, polypropylene glycol, glycerol or ethanol or complexing agentssuch as hydroxy-propyl β-cyclodextrin may be used to aid formulation.

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. Tablets may be enteric coated byconventional means, for example to provide a coating of celluloseacetate phthalate.

The invention further relates to combination therapies or compositionswherein the compounds of formula (I), (Ib) or (Ic), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising the compounds of formula (I), (Ib) or (Ic), or apharmaceutically acceptable salt thereof, is administered concurrently(possibly in the same composition) or sequentially with one or moreagents for the treatment of any of the above disease states.

For example, for the treatment of rheumatoid arthritis, osteoarthritis,COPD, asthma or allergic rhinitis a compounds of formula (I), (Ib) or(Ic), or a pharmaceutically acceptable salt thereof, can be combinedwith one or more agents for the treatment of such a condition. Wheresuch a combination is to be administered by inhalation, then the one ormore agents is selected from the list comprising:

-   -   a PDE4 inhibitor including an inhibitor of the isoform PDE4D;    -   a selective β.sub2. adrenoceptor agonist such as metaproterenol,        isoproterenol, isoprenaline, albuterol, salbutamol, formoterol,        salmeterol, terbutaline, orciprenaline, bitolterol mesylate,        pirbuterol or indacaterol;    -   a muscarinic receptor antagonist (for example a M1, M2 or M3        antagonist, such as a selective M3 antagonist) such as        ipratropium bromide, tiotropium bromide, oxitropium bromide,        pirenzepine or telenzepine;    -   a steroid (such as budesonide);    -   a modulator of chemokine receptor function (such as a CCR1        receptor antagonist);    -   an inhibitor of p38 kinase function;    -   an inhibitor of matrix metalloproteases, most preferably        targeting MMP-2, -9 or MMP-12; or,    -   an inhibitor of neutrophil serine proteases, most preferably        neutrophil elastase or proteinase 3.    -   In another embodiment of the invention where such a combination        is for the treatment of COPD, asthma or allergic rhinitis, the        compounds of formula (I), (Ib) or (Ic), or a pharmaceutically        acceptable salt thereof, can be administered by inhalation or by        the oral route and the other agent, e.g. xanthine (such as        aminophylline or theophylline) can be administered by inhalation        or by the oral route. The compounds of formula (I), (Ib) or        (Ic), or a pharmaceutically acceptable salt thereof, and the        other agent, e.g xanthine may be administered together. They may        be administered sequentially. Or they may be administered        separately.

EXAMPLES

The following Examples illustrate the invention. The followingabbreviations are used in the Examples:

TFA Trifluoroacetic acid;

THF Tetrahydrofuran

DCM Dichloromethane

HPLC High Performance Liquid Chromatography;

LC/MS Liquid Column Chromatography/Mass Spectroscopy;

GC Gas Chromatography

DMSO Dimethylsulfoxide;

APCI-MS Atmospheric Pressure Chemical Ionisation Mass Spectroscopy;

NMP 1-methyl-2-pyrrolidinone

DIEA N,N-diisopropylethylamine

HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate r.t. Room temperature, which is a temperature in therange from of 16° C. to 25° C.

General Methods

NMR spectra were recorded on a Varian Mercury-VX 300 MHz instrument or aVarian Inova 400 MHz instrument. The central peaks of chloroform-d (H7.27 ppm), acetone (H 2.05 ppm), dichloromethane-d2 (H 5.32 ppm) orDMSO-d₆ (H 2.50 ppm) were used as internal references. Alternatively,NMR spectra were recorded on a Varian Inova Unity 500 MHz instrument.Proton-NMR experiments were acquired using dual suppression of residualsolvent peak and H₂O.

The following method was used for LC/MS analysis:

Instrument Agilent 1100; Column Waters Symmetry 2.1×30 mm; Mass APCI;Flow rate 0.7 mL/min; Wavelength 254 nm; Solvent A: water+0.1% TFA;Solvent B: acetonitrile+0.1% TFA; Gradient 15-95%/B 2.7 min, 95% B 0.3min.

The following method was used for GC-MS analysis:

Low resolution mass spectra and accurate mass determination wererecorded on a Hewlett-Packard GC. MS system equipped with EI ionisationchamber, 70 eV.

The following method was used for LC analysis:

Method A. Instrument Agilent 1100; Column: Kromasil C18 100×3 mm, 5μparticle size, Solvent A: 0.1% TFA/water, Solvent B: 0.08%TFA/acetonitrile Flow: 1 mL/min, Gradient 10-100%/B 20 min, 100% B 1min. Absorption was measured at 220, 254 and 280 nm.

A Kromasil KR-100-5-C18 column (250×20 mm, Akzo Nobel) and mixtures ofacetonitrile/water (0.1% TFA) at a flow rate of 10 mL/min was used forpreparative HPLC. Unless stated otherwise, starting materials werecommercially available. All solvents and commercial reagents were oflaboratory grade and were used as received.

Example 1N-((1S,2R)-2-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl)cyclopropanecarboxamide

To a stirred solution of(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(18 mg, 50 μmol) in dichloromethane (2 ml) was added triethylamine (100μl), followed by cyclopropanecarbonyl chloride (15 mg, 150 μmol). Thestirring was continued for 20 min at r.t., then the solvent was removedunder reduced pressure, and the product purified by semi-preparativeHPLC. Yield 20 mg (95%).

APCI-MS: m/z 430 [MH⁺]

1H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.5 Hz, 1H), 7.77 (m, 2H),7.71 (d, J=9.2 Hz, 1H), 7.58 (br.d, J=7.8 Hz, 1H), 7.46 (d, J=7.3 Hz,2H), 7.35 (m, 4H), 7.28 (d, J=7.4 Hz, 1H), 7.25 (dd, J=9.2, 2.3 Hz, 1H),7.10 (d, J=2.3 Hz, 1H), 5.51 (d, J=3.5 Hz, 1H), 4.32 (m, 1H), 1.58(septet, J=4.2 Hz, 1H), 1.19 (d, J=6.9 Hz, 3H), 0.79 (m, 1H), 0.71 (m,1H), 0.67-0.53 (m, 2H).

(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-amine(1a)

The title compound was prepared essentially by the method described byJob & Buchwald: Org. Lett. 2002, 4 (21), 3703-3706.

1-(Fluorophenyl)-5-iodoindazole (43 mg, 0.12 mmol), (1R,2S)-norephedrine(16 mg, 0.1 mmol), copper (I) iodide (2.2 mg, 5 mol %) and caesiumcarbonate (84 mg, 0.26 mmol) were suspended in butyronitrile (1 mL). Thereaction vessel was capped and the mixture was stirred at 125° C. Theprogress of the reaction was followed by HPLC (R.P. C-18, 20-90%gradient of CH₃CN in water, 0.1% TFA). After 7.5 h additional(1R,2S)-norephedrine (70 mg), copper (I) iodide (16 mg) and caesiumcarbonate (136 mg) were added and the stirring was continued at 125° C.After 2 h all 1-(fluorophenyl)-5-iodoindazole was consumed and themixture was cooled, filtered and evaporated. Flash chromatography (SiO₂,gradient of 0-30% MeOH in EtOAc) gave the title compound (19 mg, 41%).

APCI-MS m/z: 362.2 [MH⁺].

¹H-NMR (300 MHz, DMSO-d+D₂O, TfA added): 8.16 (1H, d), 7.76-7.68 (3H,m), 7.43-7.28 (8H, m), 7.12 (1H, d), 5.64 (1H, d), 3.70 (1H, qd), 1.16(3H, d).

¹⁹F-NMR (DMSO-d₆): −115.97 (tt, unresolved).

Example 22,2,2-Trifluoro-N-((1S,2R)-2-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl)acetamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and trifluoroacetic anhydride (31 mg, 150 μmol).Yield 18 mg (78%).

APCI-MS: m/z 458 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.62 (br.d, J=7.8 Hz, 1H), 8.03 (d, J=0.7Hz, 1H), 7.77 (m, 3H), 7.70 (d, J=9.2 Hz, 1H), 7.49 (d, J=7.3 Hz, 2H),7.34 (m, 4H), 7.24 (dd, J=9.1, 2.4 Hz, 1H), 7.15 (d, J=2.3 Hz, 1H), 5.51(d, J=4.8 Hz, 1H), 4.44 (m, 1H), 1.38 (d, J=6.9 Hz, 3H).

Example 3N-((1S,2R)-2-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl)propanamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 14 mg, 38 μmol) and propanoyl chloride (10 mg, 114 μmol). Yield 14mg (90%).

APCI-MS: m/z 418 [MH⁺]

1H NMR (400 MHz, d₆-acetone) δ 8.03 (d, J=0.7 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.0 Hz, 1H), 7.46 (d, J=7.1 Hz, 2H), 7.38-7.26 (m, 5H), 7.23(dd, J=9.2, 2.5 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 5.48 (d, J=3.9 Hz, 1H),4.33 (m, 1H), 2.13 (m, 2H), 1.19 (d, J=6.9 Hz, 3H), 0.99 (t, J=7.6 Hz,3H).

Example 4 Methyl((1S,2R)-2-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-methyl-2-phenylethyl)carbamate

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 14 mg, 38 μmol) and methyl chlorocarbonate (11 mg, 114 μmol). Yield14 mg (90%).

APCI-MS: m/z 420 [MH⁺]

1H NMR (400 MHz, d₆-acetone) δ 8.03 (s, 1H), 7.77 (m, 2H), 7.70 (d,J=9.0 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.40-7.26 (m, 5H), 7.24 (dd,J=9.1, 2.4 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 6.43 (br.d, J=7.8 Hz, 1H),5.46 (d, J=3.5 Hz, 1H), 4.06 (m, 1H), 3.54 (s, 3H), 1.23 (d, J=6.9 Hz,3H).

Example 5N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-hydroxy-2-methyl-propanamide

To a stirred solution of(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(18 mg, 50 μmol) in dichloromethane (2 ml) was added triethylamine (100μl), followed by 2-chloro-1,1-dimethyl-2-oxoethyl acetate (24 mg, 150μmol). The stirring was continued for 20 min at r.t., then the solventwas removed under reduced pressure, and the residue dissolved in ethanol(1 ml). Aqueous sodium hydroxide solution (1 M, 1 ml) was added, and themixture was stirrer at 80° C. for 30 min. Then it was cooled to r.t.,acidified with TFA, and concentrated under reduced pressure. The productwas purified by semi-prep. HPLC. Yield 22 mg (96%).

APCI-MS: m/z 448 [MH⁺]

1H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.7 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.0 Hz, 1H), 7.49 (d, J=7.4 Hz, 2H), 7.43-7.27 (m, 5H), 7.25(dd, J=9.1, 2.4 Hz, 1H), 7.15 (d, J=2.3 Hz, 1H), 5.48 (d, J=4.6 Hz, 1H),4.33 (m, 1H), 1.30 (s, 3H), 1.23 (d, J=6.7 Hz, 3H), 1.20 (s, 3H).

Example 62,2,2-Trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]acetamide

Prepared as described in Example 1 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(90 mg, 230 μmol) and trifluoroacetic anhydride (98 mg, 460 μmol). Yield101 mg (90%).

APCI-MS: m/z 488 [MH⁺]

1H NMR (400 MHz, d₆-acetone) δ 8.60 (br.d, J=8.1 Hz, 1H), 8.05 (d, J=0.9Hz, 1H), 7.77 (m, 2H), 7.71 (d, J=9.0 Hz, 1H), 7.32 (m, 3H), 7.24 (dd,J=9.1, 2.4 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 7.06 (m, 2H), 6.87 (m, 1H),5.48 (d, J=4.8 Hz, 1H), 4.44 (m, 1H), 3.78 (s, 3H), 1.38 (d, J=6.9 Hz,3H).

(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a)

1-(Fluorophenyl)-5-iodo-1H-indazole (338 mg, 1 mmol),(1R,2S)-2-amino-1-(3-methoxyphenyl)propan-1-ol (220 mg, 1.2 mmol),copper (I) iodide (19 mg, 100 μmol, 10 mol %), and cesium carbonate (764mg, 2 mmol) were suspended in butyronitrile (2 ml). The reaction vesselwas capped and the mixture was stirred at 125° C. for 5 h. Then themixture was cooled, the precipitate removed by filtration and washedwith ethyl acetate (10 ml). The combined organic solutions wereconcentrated under reduced pressure. The product was isolated by flashchromatography on silica gel (gradient of 0-30% MeOH in EtOAc) to affordthe subtitle compound (148 mg, 38%).

APCI-MS m/z: 392 [MH⁺].

¹H-NMR (400 MHz, CD₃OD): 7.88 (d, J=1.8 Hz, 1H), 7.54 (m, 2H), 7.46 (d,J=8.8 Hz, 1H), 7.24-7.12 (m, 4H), 7.02 (d, J=1.6 Hz, 1H), 6.95 (m, 2H),6.78 (m, 1H), 5.04 (d, J=5.1 Hz, 1H), 3.70 (s, 3H), 3.22 (quintet, J=6.1Hz, 1H), 1.15 (d, J=6.7 Hz, 3H)

(1R,2S)-2-amino-1-(3-methoxyphenyl)propan-1-ol (6b)

To a stirred solution of tert-butyl[(1S,2R)-2-hydroxy-2-(3-methoxyphenyl)-1-methylethyl]carbamate (317 mg,1.13 mmol) in dichloromethane (3 ml) was added water (3 ml), and TFA (5ml), so that a clear solution has been obtained. The mixture was stirredat r.t. for 1 h, than poured into water (30 ml). The aqueous layer waswashed with dichloromethane (30 ml), and made alkaline (pH≈10) byaddition of 10 N aqueous NaOH. Brine (20 ml) was added, and the solutionwas extracted with dichloromethane (3×30 ml). The extracts were driedwith Na₂SO₄, and the solvent was removed under reduced pressure toafford the subtitle compound as colourless oil. Yield 179 mg (88%).

APCI-MS m/z: 182 [MH⁺].

¹H-NMR (400 MHz, CDCl₃): δ 7.24 (d, J=8.3 Hz, 1H), 6.90 (m, 2H), 6.81(m, 1H), 4.53 (d, J=4.6 Hz, 1H), 3.81 (s, 3H), 3.19 (dt, J=11.3, 6.5 Hz,1H), 0.98 (d, J=6.5 Hz, 3H)

tert-Butyl[(1S,2R)-2-hydroxy-2-(3-methoxyphenyl)-1-methylethyl]carbamate (6c)

Synthesized analogously to the method described by J. Yin et al, J. Org.Chem., 71, 840-843 (2006).

A mixture of tert-butyl[(1S)-2-(3-methoxyphenyl)-1-methyl-2-oxoethyl]carbamate (13.6 g, 48.7mmol), aluminum isopropoxide (1.99 g, 9.70 mmol), 2-propanol (41 mL, 535mmol) in toluene (63 mL) was stirred under an atmosphere of argon at 50°C. overnight. LC/MS showed complete conversion into the alcohol. Themixture was partitioned between ethyl acetate (200 mL) and hydrochloricacid (1M, 200 mL). The organic phase was washed with water (200 mL),dried over magnesium sulfate and concentrated to give the subtitlecompound as a syrup (13.5 g). The compound was used in the next stepwithout further purification.

¹H-NMR (400 MHz, CDCl₃): δ 7.27 (t, J=8.0 Hz, 1H), 6.93 (m, 2H), 6.83(dd, J=8.0, 2.2 Hz, 1H), 4.85 (d, J=2.8 Hz, 1H), 4.00 (br.s, 1H), 3.83(s, 3H), 3.04 (br.s, 1H), 1.48 (s, 9H), 1.01 (d, J=6.9 Hz, 3H).

tert-Butyl [(1S)-2-(3-methoxyphenyl)-1-methyl-2-oxoethyl]carbamate (6d)

To a stirred solution ofN²-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-alaninamide (777 mg, 3.3mmol) in dry THF (50 ml) was added a solution ofbromo(3-methoxyphenyl)magnesium (1M in THF, 10 ml, 10 mmol). The mixturewas stirred at r.t. for 5 h, then quenched with saturated aqueous NH₄Cl(50 ml). After stirring for 30 min, the layers were separated, theaqueous layer extracted with ethyl acetate (50 ml). The combined organiclayers were dried with Na₂SO₄, and the solvent was removed in vacuo. Thesubtitle compound was isolated by flash chromatography on silica gel(n-heptane/ethyl acetate, gradient from 20 to 50% ethyl acetate). Yield471 mg (94%).

¹H-NMR (400 MHz, CDCl₃): δ 7.55 (d, J=7.6 Hz, 1H), 7.49 (t, J=1.9 Hz,1H), 7.39 (t, J=8.0 Hz, 1H), 7.15 (dd, J=8.2, 2.0 Hz, 1H), 5.56 (d,J=6.9 Hz, 1H), 5.28 (quintet, J=7.2 Hz, 1H), 3.86 (s, 3H), 1.47 (s, 9H),1.41 (d, J=7.1 Hz, 3H).

Example 7N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-hydroxy-acetamide

Prepared as described in Example 5 using(1R,2S)-1-(4-ethylphenyl)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}propan-2-amine(20 mg, 50 μmol) and 2-chloro-2-oxoethyl acetate (21 mg, 150 μmol).Yield 21 mg (91%).

APCI-MS: m/z 448 [MH⁺]

1H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.5 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.2 Hz, 1H), 7.41-7.30 (m, 5H), 7.23 (m, 3H), 7.13 (d, J=2.1Hz, 1H), 5.48 (d, J=3.9 Hz, 1H), 4.39 (m, 1H), 3.91 (dd, J=16.8, 15.9Hz, 2H), 2.62 (q, J=7.5 Hz, 2H), 1.21 (d, J=6.9 Hz, 3H), 1.19 (t, J=7.6Hz, 3H)

(1R,2S)-1-(4-ethylphenyl)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}propan-2-amine(7a)

Prepared as described in Example 6 (Step 6a), using(1R,2S)-2-amino-1-(4-ethylphenyl)propan-1-ol (440 mg, 1.3 mmol). Yield239 mg (47%).

APCI-MS: m/z 390 [MH⁺]

1H NMR (400 MHz, d₆-DMSO) δ 8.16 (s, 1H), 7.71 (m, 3H), 7.38 (t, J=8.8Hz, 2H), 7.30 (m, 3H), 7.23 (d, J=8.0 Hz, 2H), 7.13 (d, J=2.3 Hz, 1H),5.59 (d, J=3.0 Hz, 1H), 3.65 (m, 1H), 2.56 (q, J=7.5 Hz, 2H), 1.14 (m,6H)

(1R,2S)-2-Amino-1-(4-ethylphenyl)propan-1-ol (7b)

To a stirred solution of tert-butyl[(1S,2R)-2-(4-ethylphenyl)-2-hydroxy-1-methylethyl]carbamate (450 mg,1.51 mmol) in acetonitrile (10 ml) was added aq. HCl (6 N, 3 ml), andstirring was continued for 3.5 h. Then the mixture was diluted withwater (10 ml), and acetonitrile was removed in vacuo. The mixture waswashed with dichloromethane (20 ml). The aqueous layer was then madealkaline (pH≈10) by addition of aq. NaOH (10 N), and extracted withdichloromethane (3×20 ml). The combined organic extracts were dried withNa₂SO₄, the solvent was removed in vacuo to afford white solid, 280 mg(97%).

APCI-MS: m/z 180 [MH⁺]

1H NMR (400 MHz, d₆-DMSO) δ 7.20 (d, J=8.0 Hz, 3H), 7.14 (d, J=8.1 Hz,3H), 5.05 (br.s, 1H), 4.26 (d, J=4.8 Hz, 1H), 2.85 (quintet, J=6.1 Hz,1H), 2.58 (q, J=7.6 Hz, 2H), 1.17 (t, J=7.6 Hz, 3H), 0.85 (d, J=6.4 Hz,3H).

tert-Butyl [(1S,2R)-2-(4-ethylphenyl)-2-hydroxy-1-methylethyl]carbamate(7c)

The procedure described by J. Yin et al., J. Org. Chem. 2006, 71,840-843) was used. A mixture of tert-butyl[(1S)-2-(4-ethylphenyl)-1-methyl-2-oxoethyl]carbamate (555 mg, 2 mmol),Al(iPr)₃ (81 mg, 0.4 mmol), 2-propanol (1.32 g, 22 mmol), and toluene(2.6 ml, 1.3 ml/mmol) was heated in a sealed vial at 50° C. overnight.Then the reaction mixture was cooled to r.t., quenched with aqueous HCl(1 N, 10 ml), and diluted with ethyl acetate (10 ml). The layers wereseparated, the organic layer was washed with water (80 ml), dried withNa₂SO₄, and concentrated. Trituration with n-heptane (30 ml) affordedthe subtitle compound as colourless precipitate, 137 mg. n-Heptanesolution was concentrated under reduced pressure, and the residuepurified by flash chromatography in silica gel to give the second cropof the subtitle compound, 318 mg. Overall yield 455 mg (81%).

1H NMR (400 MHz, CDCl₃) δ 7.26 (d, J=8.1 Hz, 2H, partially covered withthe signal of solvent), 7.19 (d, J=8.1 Hz, 2H), 4.83 (d, J=2.7 Hz, 1H),4.62 (br.s, 1H), 4.01 (br.s, 1H), 2.65 (q, J=7.5 Hz, 2H), 1.47 (s, 9H),1.24 (t, J=7.6 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H).

tert-Butyl [(1S)-2-(4-ethylphenyl)-1-methyl-2-oxoethyl]carbamate (7d)

To a stirred suspension of magnesium turnings (243 mg, 10 mmol) in dryTHF (10 ml) was added a solution of 1-bromo-4-ethylbenzene (1.85 g, 10mmol) in dry THF (10 ml), followed by a small crystal of iodine. Thereaction mixture was heated with reflux for 4 h, then cooled to r.t. Asolution of N²-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-alaninamide(464 mg, 2 mmol) in dry THF (15 ml) was added dropwise, and the stirringwas continued for 5 h at r.t. Then the reaction mixture was quenchedwith sat. aqueous NH₄Cl (25 ml) stirred for 30 min, and the layers wereseparated. The aqueous layer extracted with ethyl acetate (50 ml). Thecombined organic layers were dried with Na₂SO₄, and the solvent wasremoved under reduced pressure to give the subtitle compound ascolourless oil, 718 mg, 70% purity (as determined by NMR). Used in thenext step without further purification.

1H NMR (400 MHz, CDCl₃) δ 7.90 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz,2H), 5.60 (br.d, J=5.8 Hz, 1H), 5.28 (quintet, J=7.0 Hz, 1H), 2.73 (q,J=7.6 Hz, 2H), 1.47 (s, 9H), 1.41 (d, J=7.1 Hz, 3H), 1.27 (t, J=7.6 Hz,3H).

Example 8N-{2-[1-(4-Fluoro-phenyl)-1H-indazo-5-yloxy]-2-(3-methoxy-phenyl)-1-methyl-ethyl}-2,2-dimethyl-propionamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(6a, 110 mg, 200 μmol) and pyvaloyl chloride (0.070 ml, 560 μmol). Yield86 mg (90%).

APCI-MS: m/z 476.1 [MH⁺]

1H NMR (400 MHz, d₆-DMSO) δ 8.18 (br, 1H), 7.76-7.62 (m, 3H), 7.39 (t,J=8.7 Hz, 2H), 7.33 (d, J=8.5 Hz 1H), 7.27-7.18 (m, 2H), 7.10 (d, J=2Hz, 1H), 7.0-6.94 (m, 2H), 6.81 (d, J=8.6 Hz 1H), 5.26 (d, J=6.2 Hz,1H), 4.18 (m, 1H), 3.73 (s, 3H), 1.22 (d, J=6.7 Hz, 3H), 0.95 (s, 9H).

Example 9N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]-2-methoxy-acetamide

Methoxyacetyl chloride (10 μL, 0.11 mmol) was added to a suspension of(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-aminehydrochloride (40 mg, 0.09 mmol) and triethylamine (42 μL, 0.3 mmol) inTHF (1 mL). The reaction was stirred at r.t. for 30 min and thenquenched by adding water, the mixture was diluted with a small volume ofMeCN so that a solution was obtained. This crude mixture was purified bysemi-preparative HPLC using a Kromasil® C18 250×20 mm, 5 μm column. Flow10 mL/min, 20 min gradient of 20%-90% MeCN in water followed byisocratic final concentration until product had eluted. UV=254 nm wasused for detection. Fractions with product was combined and lyophilizedto afford the title compound as a colourless solid. Yield 30 mg (69%).

APCI-MS: m/z 480.1 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.17 (d, J=0.8 Hz, 1H), 7.80-7.70 (m, 3H),7.68 (d, J=9.16 Hz, 1H), 7.45-7.30 (m, 4H), 7.25-7.16 (m, 3H), 7.10 (d,J=2.12 Hz, 1H), 5.33 (d, J=5.97 Hz, 1H), 4.23 (m, 1H), 3.70 (dd, 2H),3.20 (s, 3H), 2.43 (s, 3H), 1.21 (d, J=6.77 Hz, 3H).

(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-aminehydrochloride (9a)

(1R,2S)-2-Amino-1-[4-(methylthio)phenyl]propan-1-ol (595 mg, 3 mmol),1-(fluorophenyl)-5-iodoindazole (913 mg, 2.7 mmol), CuI (28 mg, 0.15mmol) and Cs₂CO₃ (1.95 g, 6 mmol) was suspended in butyronitrile (5 mL)and toluene (2 mL). The reaction vessel was sealed and the mixture wasstirred at +125° C. for 6 h. The reaction mixture was cooled down andpartitioned between EtOAc and water, the water phase was extracted oncewith EtOAc. The combined organic phases was concentrated and purified bysemi-preparative HPLC using a Kromasil® C18 250×20 mm, 5 μm column. Flow10 mL/min, 20 min gradient of 20%-90% MeCN in water. UV=254 nm was usedfor detection. Fractions with product was combined and solvents removedby evaporation. This material was further purified by dissolving it inEtOAc and applying it onto a short silica column, the impurity could bewashed out using EtOAc as eluent, the desired product was eluted byusing an 0.35 N NH₃ in 5% MeOH/EtOAc solution, (prepared by diluting 1volume of commercially available 7 N NH₃ in MeOH with 19 volumes ofEtOAc). The solvents were evaporated and the residual material wasevaporated from MeOH several times. The residual sticky material wasdissolved in MeCN and 5-6N HCl in 2-propanol was added, the solvent wasthen removed by evaporation to afford the subtitle compound as a beigesolid salt. Yield 300 mg (25%).

APCI-MS: m/z 408.1 [MH⁺—HCl]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.40 (brs, 3H), 8.20 (d, J=0.93 Hz, 1H),7.79-7.71 (m, 3H), 7.45-7.24 (m, 7H), 7.14 (d, J=2.26 Hz), 5.69 (d,J=2.92 Hz, 1H), 3.65 (brm, 1H), 2.45 (s, 3H), 1.19 (d, J=6.77 Hz, 3H).

(1R,2S)-2-amino-1-[4-(methylthio)phenyl]propan-1-ol (9b)

The subtitle compound was prepared following a procedure described by:M. Osorio-Olivares et al. Bioorg. Med. Chem. 12 (2004) 4055-4066.

(S)-2-Trifluoroacetamido-1-(4-methylthiophenyl)-1-propanone (1.9 g, 6.6mmol; M. Osorio-Olivares et al. Tetrahedron: Asymmetry 14 (2003)1473-1477) was dissolved in 99.5% EtOH (65 mL). NaBH₄ (1.24 g, 33 mmol)was added and the mixture was stirred at r.t. for 19 h. The solventswere removed by evaporation, water (75 mL) was added, the mixture wasextracted with DCM (2×75 mL), the organic phase was dried over Na₂SO₄,filtered and concentrated. The residual oil was dissolved in Et₂O and5-6N HCl in 2-propanol (10 mL) was added, the precipitated salt wascollected and washed with ether. Obtained 1.46 g (96% yield) as thehydrochloride salt. NMR showed an 84:16 mixture of the two possiblediasteromers. The major diastereomer was isolated by preparative HPLCusing an XTerra® Prep MS C₁₈ OBD™ Column, 5 μm, 19×50 mm. 20 mingradient of 10-30% MeCN in (Water+2 mL NH₃/L). The purest fractions wascombined and lyophilized to afford the subtitle compound as a colourlesssolid. Yield 595 mg (45%).

APCI-MS: m/z 198.1 [MH⁺]

¹H-NMR (300 MHz, CD₃OD): δ 7.33-7.24 (m, 4H), 4.54 (d, J=4.91 Hz, 1H),3.13 (m, 1H), 2.47 (s, 3H), 1.05 (d, J=6.63 Hz, 3H).

Example 10N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]carbamoylmethylacetate

Acetoxyacetyl chloride (32 μL, 0.3 mmol) was added to a solution of(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-aminehydrochloride (9a) (97 mg, 0.22 mmol) and N-ethyldiisopropylamine (120μL, 0.7 mmol) in THF (2 mL). The reaction mixture was stirred at r.t.for 1 h, another portion of reagents was added, N-ethyldiisopropylamine(120 μL, 0.7 mmol) and acetoxyacetyl chloride (32 μL, 0.3 mmol), afteranother 15 min the reaction was quenced by addition of water. Thereaction mixture was concentrated and purified by semi-preparative HPLCusing a Kromasil® C18 250×20 mm, 5 μm column. Flow 10 mL/min, 20 mingradient of 20%-90% MeCN in water followed by isocratic finalconcentration until product had eluted. UV=254 nm was used fordetection. Fractions with product was combined and lyophilized to affordthe title compound as a colourless solid. Yield 67 mg (60%).

APCI-MS: m/z 508.1 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.17 (d, J=7.2 Hz, 1H), 8.16 (d, J=0.92 Hz,1H), 7.78-7.66 (m, 3H), 7.44-7.17 (m, 7H), 7.09 (d, J=2.12 Hz, 1H), 5.31(d, J=4.77 Hz, 1H), 4.40 (dd, 2H), 4.15 (m, 1H), 2.44 (s, 3H), 2.06 (s,3H), 1.17 (d, J=6.9 Hz, 3H).

Example 11N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]-2-hydroxy-acetamide

N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]carbamoylmethylacetate (10) (47 mg, 0.09 mmol) was dissolved in MeOH (5 mL), water (1mL) and 28% NH₃ (aq) (1 mL). The solution was stirred at r.t. for 1 h.MeOH was removed by evaporation and the residual material was dilutedwith water, the formed slurry was lyophilized to afford the titlecompound as a colourless solid. Yield 36 mg (89%)

APCI-MS: m/z 465.9 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.16 (d, J=0.80 Hz, 1H), 7.78-7.66 (m, 3H),7.63 (d, J=8.89 Hz, 1H), 7.44-7.30 (m, 4H), 7.25-7.16 (m, 3H), 7.10 (d,J=2.12 Hz, 1H), 5.51 (t, J=5.7 Hz, 1H), 5.38 (d, J=5.31 Hz, 1H), 4.24(m, 1H), 3.74 (m, 2H), 2.43 (s, 3H), 1.19 (d, J=6.77 Hz, 3H).

Example 12N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfonylphenyl)propan-2-yl]-2-hydroxy-acetamide

N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]-2-hydroxy-acetamide(11) (80 mg, 0.17 mmol) was dissolved in AcOH (1 mL), hydrogen peroxide,35% (1 mL, 12.14 mmol) was added and the mixture was stirred at +60° C.for 1.5 h. The reaction mixture was lyophilized to give a crude productas an sticky oil. The crude product was further purified by HPLC usingan XBridge™ Prep C18 5 μm OBD™ 30×150 mm column [Flow=20 mL/min, 30 mingradient of 10-60% MeCN in (H2O+2 mL NH₃/L), UV=220 nm was used fordetection]. The fractions containing the product was combined andlyophilized to afford the title compound as an colourless solid. Yield26 mg (30%)

APCI-MS: m/z 498.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 8.17 (d, J=0.61 Hz, 1H), 7.91 (d, J=8.31Hz, 2H), 7.78-7.65 (m, 6H), 7.40 (m, 2H), 7.24 (dd, J=9.2, 2.48 Hz, 1H),7.13 (d, J=2.3 Hz, 1H), 5.55 (d, J=5.48 Hz, 1H), 5.51 (t, J=4.95 Hz,1H), 4.28 (m, 1H), 3.72 (m, 2H), 3.19 (s, 3H), 1.21 (d, J=6.72 Hz, 3H).

Example 132,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]acetamide

(1R,2S)-1-{[1-(4-Fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-aminehydrochloride (9a) (150 mg, 0.34 mmol) was dissolved in MeOH (2 mL).1,1,3,3-tetramethylguanidine (128 μL, 1.02 mmol) was added and themixture was stirred for 5 min, ethyl trifluoroacetate (83 μL, 0.7 mmol)was added and the reaction mixture was stirred at r.t. for 2.5 h. Thereaction mixture was evaporated and the residual material was purifiedby semi-preparative HPLC using a Kromasil® C18 250×20 mm, 5 μm column.Flow 10 mL/min, 20 min gradient of 20%-90% MeCN in water followed byisocratic final concentration until product had eluted. UV=254 nm wasused for detection. Fractions with product was combined and lyophilizedto afford the title compound as a colourless solid. Yield 128 mg (74%)

APCI-MS: m/z 504.1 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 9.51 (d, J=8.36 Hz, 1H), 8.17 (d, J=0.79Hz, 1H), 7.78-7.66 (m, 3H), 7.44-7.30 (m, 4H), 7.26-7.16 (m, 3H), 7.11(d, J=2.13 Hz, 1H), 5.27 (d, J=6.37 Hz, 1H), 4.23 (m, 1H), 2.43 (s, 3H),1.32 (d, J=6.77 Hz, 3H).

Example 14N-[(1R,2S)-1-(4-Ethylsulfanylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

(1R,2S)-2-Amino-1-[4-(ethylthio)phenyl]propan-1-ol (526 mg, 2.49 mmol),1-(fluorophenyl)-5-iodoindazole (676 mg, 2 mmol), CuI (24 mg, 0.13 mmol)and Cs₂CO₃ (1.6 g, 5 mmol) was suspended in butyronitrile (5 mL) andtoluene (0.5 mL). The reaction vessel was sealed and the mixture wasstirred at +125° C. for 6 h. The reaction mixture was cooled down andpartitioned between EtOAc and water, the water phase was extracted oncewith EtOAc. The organic phase was filtered through a short silica columnand impurities was washed out with EtOAc, the crude intermediate productwas eluted using a 0.35N NH₃ 5% MeOH/EtOAc (prepared by diluting 1volume of commercially available 7 N NH₃ in MeOH with 19 volumes ofEtOAc). Solvents were removed by evaporation to give 515 mg of crudeintermediate amine(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(ethylthio)phenyl]propan-2-amine.

APCI-MS: m/z 422.1 [MH⁺], the major impurity being unreacted(1R,2S)-2-amino-1-[4-(ethylthio)phenyl]propan-1-ol.

The crude amine was dissolved in MeOH (15 mL) and treated with excess1,1,3,3-tetramethylguanidine (629 μL, 5 mmol) and ethyl trifluoroacetate(595 μL, 5 mmol). The reaction mixture was stirred at r.t. for 1 h,concentrated and purified by HPLC using a Kromasil® 100-10-C18 250×50 mmcolumn. Flow 40 mL/min, 10 min gradient of 50%-90% MeCN in waterfollowed by isocratic final concentration for 30 min until product hadeluted. UV=254 nm was used for detection. Fractions with product wascombined and lyophilized to afford the title compound as a colourlesssolid. Yield 380 mg (36%).

APCI-MS: m/z 518.1 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 9.49 (d, J=8.63 Hz, 1H), 8.17 (d, J=0.8 Hz,1H), 7.78-7.66 (m, 3H), 7.46-7.23 (m, 6H), 7.19 (dd, J=9.16, 2.52 Hz,1H), 7.12 (d, J=2.13 Hz, 1H), 5.25 (d, J=6.5 Hz, 1H), 4.23 (m, 1H), 2.94(q, J=7.29 Hz, 2H), 1.33 (d, J=6.77 Hz, 3H), 1.18 (t, J=7.17 Hz, 3H)

(1R,2S)-2-amino-1-[4-(ethylthio)phenyl]propan-1-ol (14a)

The subtitle compound was prepared following a procedure described by:M. Osorio-Olivares et al. Bioorg. Med. Chem. 12 (2004) 4055-4066.

(S)-2-Trifluoroacetamido-1-(4-ethylthiophenyl)-1-propanone (1.08 g, 3.5mmol; M. Osotio-Olivares et al Tetrahedron: Asymmetry 14 (2003)1473-1477) was dissolved in 99.5% EtOH (35 mL). NaBH₄ (0.67 g, 17.7mmol) was added and the mixture was stirred at r.t. for 19 h. Solventswere removed by evaporation and the residual material was suspended inwater (50 mL) and extracted with DCM (2×50 mL). The organic phase wasdried over Na₂SO₄, filtered and concentrated, the residual oil wasdissolved in Et₂O, addition of 5-6N HCl in 2-propanol resulted in theprecipitation of an hydrochloride salt, this salt was collected byfiltration, washed with ether and dried to constant weight. Obtained 845mg (97%) of the subtitle compound as the hydrochloride salt and as a85:15 mixture of the two possible diastereomeres.

The major diastereomer was isolated by preparative HPLC using an XTerra®Prep MS C₁₈ OBD™ Column, 5 μm, 19×50 mm. 20 min gradient of 10-30% MeCNin (Water+2 mL NH₃/L). The purest fractions was combined and lyophilizedto afford the subtitle compound as a colourless solid. Yield 526 mg(71%)

APCI-MS: m/z 212.1 [MH⁺]

¹H-NMR (300 MHz, CD₃OD): δ 7.36-7.26 (m, 4H), 4.46 (d, J=5.44 Hz, 1H),3.05 (m, 1H), 2.94 (q, J=7.3 Hz, 2H), 1.28 (t, J=7.3 Hz, 3H), 1.04 (d,J=6.64 Hz, 3H).

Example 15N-[(1R,2S)-1-(4-cyclopropylsulfanylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

(1R,2S)-1-{[1-(4-Fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(cyclopropylthio)phenyl]propan-2-amine(62 mg, 0.14 mmol) was dissolved in MeOH (2 mL),1,1,3,3-tetramethylguanidine (100 μL, 0.8 mmol) and ethyltrifluoroacetate (83 μL, 0.7 mmol) was added. The mixture was stirred atr.t. for 2 h, the solvents was removed by evaporation and the residualmaterial was treated with water and a few drops of dilute HCl(aq) untilslightly acidic. The formed slurry was extracted with DCM and EtOAc, thecombined organic phases was concentrated and purified bysemi-preparative HPLC using a Kromasil® C18 250×20 mm, 5 μm column. Flow10 mL/min, 15 min gradient of 50%-90% MeCN in water followed byisocratic final concentration until product had eluted. UV=254 nm wasused for detection. Fractions with product was combined and lyophilizedto afford the title compound as a colourless solid. Yield 59 mg (79%).

APCI-MS: m/z 530.1 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 9.51 (brs, 1H), 8.18 (d, J=0.79 Hz, 1H),7.78-7.66 (m, 3H), 7.44-7.28 (m, 6H), 7.19 (dd, J=9.02, 2.39 Hz, 1H),7.13 (d, J=1.99 Hz, 1H), 5.28 (d, J=6.24 Hz, 1H), 4.24 (m, 1H), 2.23 (m,1H), 1.32 (d, J=6.77 Hz, 3H), 1.12-0.98 (m, 2H), 0.60-0.46 (m, 2H)

(1R,2S)-1-{[1-(4-Fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(cyclopropylthio)phenyl]propan-2-amine(15a)

(1R,2S)-2-Amino-1-[4-(cyclopropylthio)phenyl]propan-1-ol (103 mg, 0.46mmol), 1-(fluorophenyl)-5-iodoindazole (170 mg, 0.5 mmol), CuI (5 mg,0.03 mmol) and Cs₂CO₃ (325 mg, 1 mmol) was suspended in butyronitrile (1mL) and toluene (0.5 mL). The reaction vessel was sealed and the mixturewas stirred at +125° C. for 18 h. The reaction mixture was cooled downand diluted with EtOAc (5 mL), washed with water (2×1 mL). The organicphase was filtered through a short silica column and impurities waswashed out with EtOAc, the crude product was eluted using a 0.35N NH₃ 5%MeOH/EtOAc (prepared by diluting 1 volume of commercially available 7 NNH₃ in MeOH with 19 volumes of EtOAc). Solvents was removed byevaporation and the material was further purified by preparative HPLCusing an XTerra® Prep MS Cl, OBD™ Column, 5 μm, 19×50 mm. 15 mingradient of 20-80% MeCN in (Water+2 mL NH₃/L). The fractions containingproduct was combined and lyophilized afford the subtitle compound as ahygroscopic solid. Yield 62 mg (31%)

APCI-MS: m/z 434.1 [MH⁺]

¹H-NMR (300 MHz, CD₃OD): δ 8.00 (d, J=0.93 Hz, 1H), 7.70-7.62 (m, 2H),7.57 (dt, 1H), 7.39-7.20 (m, 7H), 7.09 (d, J=1.99 Hz, 1H), 5.11 (d,J=5.04 Hz, 1H), 3.27 (m, 1H), 2.20 (m, 1H), 1.20 (d, J=6.63 Hz, 3H),1.06 (m, 2H), 0.59 (m, 2H)

(1R,2S)-2-amino-1-[4-(cyclopropylthio)phenyl]propan-1-ol (15b)

The subtitle compound was prepared in two steps following the proceduredescribed by: M. Osorio-Olivares et al. Tetrahedron: Asymmetry 14 (2003)1473-1477, and M. Osorio-Olivares et al. Bioorg. Med. Chem. 12 (2004)4055-4066.

To a stirred solution of N-(trifluoroacetyl)-L-alanyl chloride (6.5 g,32 mmol) and cyclopropyl phenyl sulfide (5 g, 33.28 mmol) in DCM (30 mL)was added AlCl₃ (4.27 g, 32 mmol). The reaction mixture was stirred atr.t. 17 h, cooled down in an ice-water batch and slowly quenched byaddition of 1 N HCl (aq) (50 mL). The mixture was extracted with DCM(2×50 mL), the organic phase was dried over MgSO₄, filtered andevaporated to give a crude product as an oil. Addition of heptane failedto give a solid, the oil was dissolved in DCM and filtered through ashort silica gel to remove some impurities.

The crude product showed some traces of the desired(S)-2-Trifluoroacetamido-1-(4-cyclopropylthiophenyl)-1-propanone byGC/MS, m/z=317.

The crude material was dissolved in 99.5% EtOH (100 mL), NaBH₄ (1.95 g,51.5 mmol) was added, the mixture was stirred at r.t. for 19 h. LC/MSanalysis showed traces of desired product APCI-MS: m/z 224 [MH⁺]. Thesolvents were removed by evaporation, water (100 mL) was added, theformed slurry was extracted with DCM. The organic phase was concentratedand the residue was purified by preparative HPLC using an XTerra® PrepMS C₁₈ OBD™ Column, 5 μm, 19×50 mm. 20 min gradient of 10-40% MeCN in(Water+2 mL NH₃/L). The fractions containing product was combined andthe purification was repeated one more time as above. The purestfractions were combined and lyophilized to afford the subtitle compoundas a colourless hygroscopic solid. Yield 103 mg (1.4%).

APCI-MS: m/z 224.1 [MH⁺]

¹H-NMR (300 MHz, CD₃OD): δ 7.36 (d, J=8.49 Hz, 2H), 7.29 (d, J=8.36 Hz,2H), 4.44 (d, J=5.44 Hz, 1H), 3.04 (m, 1H), 2.23 (m, 1H), 1.12-1.02 (m,2H), 1.05 (d, J=6.64 Hz, 3H), 0.64-0.57 (m, 2H)

Example 16N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-hydroxy-acetamide

Prepared as described in Example 7 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 149 mg, 0.41 mmol) and 2-chloro-2-oxoethyl acetate (49 μL, 0.45mmol). Yield 125 mg (72%).

APCI-MS: m/z 420.1 [MH⁺]

¹H NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.74 (m, 2H), 7.69 (d, J=9.2Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.44-7.32 (m, 6H), 7.26 (m 1H), 7.22(dd, J=9.2, 2.3 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 5.42 (d, J=5.0 Hz, 1H),4.25 (m 1H), 3.73 (m, 2H), 2.55 (s, 1H), 1.18 (d, J=6.7 Hz, 3H).

Example 17

N-[(1R*,2S*)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]cyclopropanecarboxamide

Prepared as described in Example 1 with corresponding starting material.

APCI-MS: m/z 461.1 [MH⁺]

¹H-NMR (400 MHz, acetone-d₆) δ 8.22 (1H, d); 8.06 (1H, s); 7.80-7.69(4H, m); 7.52 (1H, d); 7.34 (2H, dd); 7.23 (2H, dd); 7.19 (1H, d); 6.74(1H, d); 5.45 (1H, d); 4.37-4.27 (1H, m); 3.85 (3H, s); 1.54 (1H, ddd);1.27 (3H, d); 0.79-0.73 (1H, m); 0.69-0.53 (3H, m).

(1R*,2S*)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-amine(17a)

Prepared as described in Example 1 with corresponding starting material.

APCI-MS: m/z 393.1 [MH⁺]

¹H-NMR (400 MHz, acetone-d₆) δ8.21 (1H, d); 8.04 (1H, d); 7.78-7.70 (3H,m); 7.65 (1H, d); 7.38-7.14 (4H, m); 6.68 (1H, d); 5.23 (1H, d); 3.98(1H, q); 3.82 (3H, s); 1.85-1.79 (1H, m); 1.65-1.58 (1H, m); 1.27 (3H,d)

(1R*,2S*)-2-amino-1-(6-methoxypyridin-3-yl)propan-1-ol1-(6-methoxypyridin-3-yl)-2-nitro-propan-1-ol (17b)

1-(6-methoxypyridin-3-yl)-2-nitro-propan-1-ol (17c) (2.20 g, 10.37 mmol)was dissolved in methanol (410 mL) and hydrogenated using a H-Cube™hydrogenation reactor (THALES nanotechnology) equipped with a cartridgeof 10% Pd/C. The flow rate was set to 0.8 mL/min, temperature 80° C. andfull the hydrogen production at full mode. After evaporation of thesolution diastereomers were separated on preparative HPLC (XTerrra C₁₈,19×50 mm) using a gradient of 5-30% acetonitrile in water (+1% NH₃) gavethe subtitle compound 17b (448 mg, 24%).

¹H-NMR (400 MHz, DMSO-d₆): δ 8.05 (1H, d); 7.63 (1H, dd); 6.76 (1H, d);4.29 (1H, d); 3.82 (3H, s); 2.90 (1H, quintet); 0.87 (3H, d).

APCI-MS: m/z 183.0 [MH⁺].

1-(6-methoxypyridin-3-yl)-2-nitro-propan-1-ol (17c)

To a round bottom flask was added anhydrous magnesium sulphate (4.77 g,40 mmol) and nitroethane (15 ml) The flask was evacuated and filled withargon. The reaction mixture was stirred vigorously to get a homogeneoussuspension before 6-methoxynicotinaldehyde (2.37 g, 18 mmol in 5 mLnitroethane) was added. After stirring in 5 min2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane,2,8,9-tris(1-methylethyl) (1082 mg, 3.6 mmol) was added. The reactionmixture was stirred overnight at r.t. before it was purified by flashchromatography (SiO₂, heptane-ethylacetate). Yield 2.22 g, 58%.

APCI-MS: m/z 213.1 [MH⁺].

(1R*,2S*)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-amine

Prepared as described in Example 1 with corresponding starting material.

APCI-MS: m/z 393.1 [MH⁺]

¹H-NMR (400 MHz, acetone-d₆) δ8.21 (1H, d); 8.04 (1H, d); 7.78-7.70 (3H,m); 7.65 (1H, d); 7.38-7.14 (4H, m); 6.68 (1H, d); 5.23 (1H, d); 3.98(1H, q); 3.82 (3H, s); 1.85-1.79 (1H, m); 1.65-1.58 (1H, m); 1.27 (3H,d).

Example 18N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]cyclopropanecarboxamide

The racemic mixture ofN-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]cyclopropanecarboxamide(16) were separated on Thales SFC, Chiralpak IA column (75% CO₂, 25%MeOH) collecting the second eluting peak.

¹H-NMR (400 MHz, Acetone-d₆) δ 8.22 (1H, d); 8.06 (1H, s); 7.80-7.69(4H, m); 7.52 (1H, d); 7.34 (2H, dd); 7.23 (2H, dd); 7.19 (1H, d); 6.74(1H, d); 5.45 (1H, d); 4.37-4.27 (1H, m); 3.85 (3H, s); 1.54 (1H, ddd);1.27 (3H, d); 0.79-0.73 (1H, m); 0.69-0.53 (3H, m).

APCI-MS: m/z 461.1 [MH⁺].

Example 19N-[(1R,2S)-1-(2,5-dioxabicyclo[4.4.0]deca-7,9,11-trien-8-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Trifluoroacetic anhydride (0.095 mL, 0.67 mmol) was added to(1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine2,2,2-trifluoroacetate (300 mg, 0.56 mmol) and triethylamine (0.235 mL,1.69 mmol) in THF (6 mL) at r.t. After 20 min another portion oftriethylamine (0.103 mL, 0.74 mmol) and Trifluoroacetic anhydride (0.050mL, 0.35 mmol) was added. The reaction mixture was stirred for another20 min, concentrated, diluted with 10% NaHSO₄ (aq) and extracted withEtOAc. The organic phase was washed with 10% NaHSO₄ (aq). The crudeproduct was further purified by HPLC. Yield 230 mg (79%)

Chiral analysis was made using a CHIRALPAK® IB, 150×0.46 mm column, 15%EtOH/iso-Hexane, 0.5 mL/min, UV=254 nm: >99% ee, Rt=15.57 min.

APCI-MS: m/z 516.1 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 9.47 (d, 1H), 8.19 (d, 1H), 7.74 (m, 2H),7.69 (d, 1H), 7.40 (m, 2H), 7.18 (dd, 1H), 7.12 (d, 1H), 6.89-6.79 (m,3H), 5.19 (d, 1H), 4.18 (s+m, 4H+1H), 1.31 (d, 3H).

(1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine2,2,2-trifluoroacetate. (19a)

The subtitle compound was prepared essentially by the method describedby Job & Buchwald: Org. Lett. 2002, 4 (21), 3703-3706.

A mixture of(1R,2S)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propan-1-olhydrochloride (246 mg, 1.00 mmol), 1-(4-fluorophenyl)-5-iodo-1H-indazole(406 mg, 1.20 mmol), copper(I) iodide (38.1 mg, 0.20 mmol) and Cs₂CO₃(979 mg, 3.00 mmol) in butyronitrile (3 mL) was heated for 5 h at +100°C. in a sealed reaction tube flushed with Argon. The reaction mixturewas cooled down, partitioned between DCM (20 mL) and water (5 mL), brine(5 mL) was added. The water phase was extracted with another portion ofDCM (20 mL). The combined DCM phases (40 mL) was filtered through a 10 gsilica column, EtOAc (40 mL) was used to wash the column. The crudeproduct was washed out from the column using 0.35 M NH₃ in 5% MeOH/EtOAc(150 mL). The solvents was removed by evaporation. The crude product wasfurther purified by HPLC. The fractions containing product were freezedried to give the TFA salt of the desired product. NMR showed 4 mol % ofsecond set of signals originating from diastereomer. Yield 125 mg (23%)

APCI-MS: m/z 420.1 [MH⁺-TFA]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.22 (d, 1H), 8.11 (brs, 3H), 7.80-7.70 (m,3H), 7.41 (m, 2H), 7.27 (dd, 1H), 7.15 (d, 1H), 6.92-6.85 (m, 3H), 5.51(d, 1H), 4.21 (s, 4H), 3.68 (brm, 1H), 1.18 (d, 3H).

(1R,2S)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propan-1-olhydrochloride. (19b)

5-6 N HCl in 2-Propanol (8 mL, 40-48 mmol) was added to tert-butyl(1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-ylcarbamate(3.1 g, 10.02 mmol) in ethyl acetate (40 mL) at +40° C. and stirred atfor 3 h. The reaction mixture was allowed to reach r.t. and concentratedby evaporation. Ether was added and the salt was collected by filtrationand washed with ether. The salt was found to be hygroscopic. Yield 2.10g (85%)

APCI-MS: m/z 210 [MH⁺—HCl]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.01 (brs, 3H), 6.87-6.76 (m, 3H), 5.93(brd, 1H), 4.79 (brt, 1H), 4.22 (s, 4H), 3.32 (brm, 1H), 0.94 (d, 3H).

tert-butyl(1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-ylcarbamate.(19c)

The diastereoselective catalytic Meerwein-Ponndorf-Verley reduction wasmade by the method described by Jingjun Yin et. al. J. Org. Chem. 2006,71, 840-843. (S)-tert-butyl1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate (3.76g, 12.23 mmol), aluminum isopropoxide (0.5 g, 2.45 mmol) and 2-propanol(12 mL, 157.75 mmol) in toluene (22 mL) was stirred at +50° C. underargon for 16 h.

The reaction mixture was poured into 1M HCl (150 mL), the mixture wasextracted with EtOAc (250 mL). The organic phase was washed with water(2×50 mL) and brine (100 mL), dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by flash-chromatography onsilica using EtOAc:Hexane (1:2) as eluent. Fractions containing productwas combined. Solvent was removed by evaporation to give the desiredproduct as a colourless solid. Yield 3.19 g (84%)

APCI-MS: m/z 236, 210, 192 [MH⁺-tBu-18, MH⁺-BOC, MH⁺-BOC-18]

¹H-NMR (300 MHz, DMSO-d₆): δ 6.80-6.70 (m, 3H), 6.51 (d, 1H), 5.17 (d,1H), 4.36 (t, 1H), 4.19 (s, 4H), 3.49 (m, 1H), 1.31 (s, 9H), 0.93 (d,3H).

(S)-tert-butyl1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate. (19d)

A suspension of (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 12.92 mmol) inTHF (30 mL) was placed under a protective atmosphere of Argon and cooleddown to −15 to −20° C., isopropylmagnesium chloride, 2M in THF (6.5 mL,13.00 mmol) was added keeping the temperature below −10° C. The slurrystarted to dissolve, temperature was allowed to reach 0° C., a freshlyprepared solution of (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)magnesiumbromide, 0.7M in THF (20 mL, 14.00 mmol) was added. The temperature wasallowed to reach r.t., the reaction mixture was stirred for 17 h. 1N HCl(300 mL) was cooled on ice bath to +10° C., the reaction mixture waspoured into the acidic water solution, TBME=tert-butyl methyl ether (300mL) was added and the mixture was transferred to a separation funnel.The water phase was back extracted with TBME (200 mL). The ether phaseswere washed with water, brine and dried (Na₂SO₄).

The crude product was purified by flash chromatography usingTBME:Heptane=1:2 as eluent. Fractions containing the product wascombined and solvents was removed by evaporation to give the subtitlecompound as a slightly yellow sticky oil/gum. Yield 3.76 g (95%)

APCI-MS: m/z 208.1 [MH⁺-BOC]

¹H-NMR (300 MHz, DMSO-d₆): δ 7.50 (dd, 1H), 7.46 (d, 1H), 7.24 (d, 1H),6.97 (d, 1H), 4.97 (m, 1H), 4.30 (m, 4H), 1.36 (s, 9H), 1.19 (d, 3H).

Example 202,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-naphthalen-2-yl-propan-2-yl]acetamide

(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(naphthalen-2-yl)propan-2-aminehydrochloride (50 mg, 0.11 mmol), 1,1,3,3-tetramethylguanidine (100 μl,0.79 mmol) and Ethyl trifluoroacetate (200 μl, 1.68 mmol) in MeOH (2.5mL) was stirred at r.t. for 1 h. The reaction mixture was concentratedby evaporation. The residual material was purified by

HPLC. Yield 37 mg (65%)

APCI-MS: m/z 508.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): 9.58 (d, 1H), 8.13 (d, 1H), 7.94-7.85 (m,4H), 7.76-7.66 (m, 3H), 7.56 (dd, 1H), 7.50 (m, 2H), 7.38 (m, 2H), 7.25(dd, 1H), 7.17 (d, 1H), 5.46 (d, 1H), 4.36 (m, 1H), 1.38 (d, 3H).

(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(naphthalen-2-yl)propan-2-aminehydrochloride. (20a)

The subtitle compound was prepared analogous to the method described inExample 19 (step 19a). (1R,2S)-2-amino-1-(naphthalen-2-yl)propan-1-olhydrochloride (238 mg, 1.00 mmol), 1-(4-fluorophenyl)-5-iodo-1H-indazole(406 mg, 1.20 mmol), Cesium carbonate (979 mg, 3.00 mmol) and copper(I)iodide (38.1 mg, 0.20 mmol) in Butyronitrile (3 mL) was heated for 19 hat +125° C. in a sealed reaction tube flushed with Argon. After finalpurification by HPLC the obtained material was isolated as a brownishcoloured hydrochloride salt from tert-butylmethylether/HCl.

Yield 171 mg (38%)

APCI-MS: m/z 412.9 [MH⁺—HCl]

¹H-NMR (400 MHz, DMSO-d₆) 8.45 (brs, 3H), 8.16 (s, 1H), 8.00-7.88 (m,4H), 7.73 (m, 3H), 7.58 (dd, 1H), 7.53 (m, 2H), 7.39 (m, 3H), 7.20 (d,1H), 5.88 (d, 1H), 3.80 (m, 1H) 1.24 (d, 3H).

(1R,2S)-2-amino-1-(naphthalen-2-yl)propan-1-ol hydrochloride. (20b)

tert-butyl (1R,2S)-1-hydroxy-1-(naphthalen-2-yl)propan-2-ylcarbamate(588 mg, 1.95 mmol) was dissolved in Ethyl acetate (20 mL). To the clearsolution was added 1.5 N HCl/EtOAc (10 mL, 15.00 mmol), the reactionmixture was stirred at +40° C. for 2 h. The resulting slurry was allowedto cool to r.t., the salt was removed by filtration, washed with etherand dried by suction in the filtration funnel.

Yield 588 mg (85%).

APCI-MS: m/z 202 [MH⁺—HCl]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.13 (brs, 3H), 7.96-7.88 (m, 4H),7.56-7.47 (m, 3H), 6.20 (d, J=4.11 Hz, 1H), 5.11 (t, 1H), 3.50 (m, 1H),0.98 (d, 3H).

tert-butyl (1R,2S)-1-hydroxy-1-(naphthalen-2-yl)propan-2-ylcarbamate.(20c)

The title compound was prepared analogous to the method described inExample 19 (step 19c), starting from tert-butyl[(1S)-1-methyl-2-(2-naphthyl)-2-oxoethyl]carbamate (350 mg, 1.17 mmol).In contrast the reaction mixture was stirred at +50° C. for 19 h, crudematerial was purified by flash chromatography on silica using a gradientof 0% to 30% EtOAc in Heptane.

Yield 309 mg (87%)

APCI-MS: m/z 202 [MH⁺-BOC]

¹H-NMR (300 MHz, DMSO-d₆): δ 7.92-7.77 (m, 4H), 7.53-7.41 (m, 3H), 6.65(d, 1H), 5.44 (d, 1H), 4.68 (t, 1H), 3.69 (m, 1H), 1.25 (s, 9H), 0.99(d, 3H).

tert-butyl [(1S)-1-methyl-2-(2-naphthyl)-2-oxoethyl]carbamate. (20d)

The subtitle compound was prepared analogous to the method described inExample 19 (step 19d), starting from (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.86 g, 8 mmol) anda freshly prepared 2-Naphthylmagnesiumbromide 1M solution in THF (8 mL,8 mmol). The obtained material was crystallised from Heptane. Yield 350mg (14%).

APCI-MS: m/z 200 [MH⁺-BOC]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.70 (s 1H), 8.11 (d, 1H), 8.00 (m, 3H),7.65 (m, 2H), 7.38 (d, 1H), 5.24 (m, 1H), 1.35 (s, 9H), 1.29 (d, 3H).

Example 21N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-naphthalen-2-yl-propan-2-yl]-2-hydroxy-acetamide

Acetoxyacetyl chloride (13 μL, 0.12 mmol) was added to a stirred mixtureof(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(naphthalen-2-yl)propan-2-aminehydrochloride (20a) (50 mg, 0.11 mmol) and N,N-diisopropylethylamine (60μL, 0.34 mmol) in THF (2 mL). The reaction mixture was stirred at r.t.45 min. Water (0.5 mL), 28% (aq) NH3 (0.5 mL) and MeOH (0.5 mL) wasadded to give a clear one-phase solution, the mixture was stirred overnight at r.t.

The reaction mixture was concentrated, the residual material waspurified by HPLC. Yield 32 mg (61%)

APCI-MS: m/z 470.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 8.13 (d, 1H), 7.94-7.86 (m, 4H), 7.76-7.66(m, 4H), 7.58 (dd, 1H), 7.49 (m, 2H), 7.38 (m, 2H), 7.27 (dd, 1H), 7.15(d, 1H), 5.57 (d, 1H), 5.51 (brs, 1H), 4.37 (m, 1H), 3.71 (q, 2H), 1.24(d, 3H).

Example 22N-[(1R,2S)-1-(3-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

(1R,2S)-1-(3-ethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-aminehydrochloride (50 mg, 0.12 mmol), 1,1,3,3-tetramethylguanidine (100 μl,0.79 mmol) and ethyl trifluoroacetate (200 μl, 1.68 mmol) in MeOH (2.5mL) was stirred at r.t. for 1 h. The reaction mixture was concentratedby evaporation, the residual material was purified by

HPLC. Yield 41 mg (72%).

APCI-MS: m/z 486.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 9.49 (d, 1H), 8.18 (s, 1H), 7.77-7.66 (m,3H), 7.39 (m 2H), 7.28-7.17 (m, 4H), 7.15-1.08 (m, 2H), 5.26 (d, 1H),4.22 (m, 1H), 2.58 (q, 2H), 1.33 (d, 3H), 1.14 (t, 3H).

(1R,2S)-1-(3-ethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-aminehydrochloride. (22a)

The subtitle compound was prepared analogous to the method described inExample 19 (step 19a). A mixture of(1R,2S)-2-amino-1-(3-ethylphenyl)propan-1-ol hydrochloride (22b, 216 mg,1.00 mmol), 1-(4-fluorophenyl)-5-iodo-1H-indazole (406 mg, 1.20 mmol),cesium carbonate (979 mg, 3.00 mmol) and copper(I) iodide (38.1 mg, 0.20mmol) in butyronitrile (3 mL) was heated for 19 h at +125° C. in asealed reaction tube flushed with Argon. After final purification byHPLC the obtained material was dissolved in tert-Butyl methyl ether, andprecipitated as the hydrochloride salt by adding a solution of 6-7 N HClin 2-propanol. Yield 199 mg (46%)

APCI-MS: m/z 390.1 [MH⁺—HCl]

¹H-NMR (400 MHz, DMSO-d₆): δ 8.39 (brs, 3H), 8.21 (s, 1H), 7.75 (m, 3H),7.44-7.14 (m, 8H), 5.70 (d, 1H), 3.67 (m, 1H), 2.61 (q, 2H), 1.17 (d,3H), 1.16 (t, 3H).

(1R,2S)-2-amino-1-(3-ethylphenyl)propan-1-ol hydrochloride. (22b)

The subtitle compound was prepared in two steps analogous to the methoddescribed in Example 19 (step 19b+19c). Starting from (S)-tert-butyl1-(3-ethylphenyl)-1-oxopropan-2-ylcarbamate (22c, 700 mg, 2.52 mmol).Yield 425 mg (78%)

APCI-MS: m/z 180 [MH⁺—HCl]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.12 (brs, 3H), 7.28 (t, 1H), 7.22-7.09 (m,3H), 5.98 (d, 1H), 4.93 (t, 1H), 3.35 (m, 1H), 2.61 (q, 2H), 1.18 (t,3H), 0.94 (d, 3H).

(S)-tert-butyl 1-(3-ethylphenyl)-1-oxopropan-2-ylcarbamate (22c)

The subtitle compound was prepared analogous to the method described inExample 19 (step 19d). Starting from (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (0.7 g, 3.01 mmol)and freshly made (3-ethylphenyl)magnesium bromide 0.9M solution in THF(5 mL, 4.50 mmol). Yield 817 mg (97%)

GC/MS: m/z=221 (M-tBu)

¹H-NMR (300 MHz, DMSO-d₆): δ 7.82-7.74 (m, 2H), 7.51-7.38 (m, 2H), 7.30(d, 1H), 5.04 (m, 1H), 2.67 (q, 2H), 1.35 (s, 9H), 1.22 (d, 3H), 1.20(t, 3H).

Example 23N-[(1R,2S)-1-(3-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-hydroxy-acetamide

The title compound was prepared analogous to the method described inExample 21 starting from(1R,2S)-1-(3-ethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-aminehydrochloride (22a) (50 mg, 0.12 mmol), and Acetoxyacetyl chloride (14μL, 0.13 mmol). Yield 37 mg (70%).

APCI-MS: m/z 448.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 8.17 (d, 1H), 7.74 (m, 2H), 7.69 (d, 1H),7.60 (d, 1H), 7.40 (m, 2H), 7.29-7.18 (m, 4H), 7.11 (m, 2H), 5.50 (t,1H), 5.40 (d, 1H), 4.24 (m, 1H), 3.74 (m, 2H), 2.59 (q, 2H), 1.16 (d,3H), 1.15 (t, 3H).

Example 242,2,2-trifluoro-N-[(1R,2S)-1-[1(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methylphenyl)propan-2-yl]acetamide

Trifluoroacetic anhydride (42 μl, 0.30 mmol) was added to a stirredsolution of(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-m-tolylpropan-2-amine2,2,2-trifluoroacetate (120 mg, 0.25 mmol) and triethylamine (103 μl,0.74 mmol) in THF (6 mL) at r.t., after 20 min another portion oftriethylamine (103 μl, 0.74 mmol) and trifluoroacetic anhydride (42 μl,0.30 mmol) was added. The reaction mixture was stirred for another 80min, concentrated, diluted with 10% NaHSO₄ (aq) and extracted withEtOAc, the organic phase was washed with another portion of 10% NaHSO₄(aq) and concentrated. The crude product was further purified bypreparative HPLC. Yield 89 mg (77%)

APCI-MS: m/z 472.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 9.52 (d, 1H), 8.17 (d, 1H), 7.78-7.66 (m,3H), 7.44-7.34 (m, 2H), 7.27-7.16 (m, 4H), 7.12-7.05 (m, 2H), 5.25 (d,1H), 4.21 (m, 1H), 2.28 (s, 3H), 1.32 (d, 3H).

(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-m-tolylpropan-2-amine2,2,2-trifluoroacetate. (24a)

The subtitle compound was prepared analogous to the method described inExample 19a, starting from (1R,2S)-2-amino-1-m-tolylpropan-1-olhydrochloride (202 mg, 1.00 mmol).

Yield 125 mg (25%).

APCI-MS: m/z 376.1 [MH⁺-TFA]

¹H-NMR (400 MHz, DMSO-d₆): δ 8.21 (d, 1H), 8.19 (brs, 3H), 7.80-7.70 (m,3H), 7.41 (m, 2H), 7.35-7.10 (m, 6H), 5.60 (d, 1H), 3.71 (brm, 1H), 2.31(s, 3H), 1.16 (d, 3H).

(1R,2S)-2-amino-1-m-tolylpropan-1-ol hydrochloride (24b)

tert-butyl (1R,2S)-1-hydroxy-1-m-tolylpropan-2-ylcarbamate (2.31 g, 8.71mmol) was dissolved in ethyl acetate (30 mL), 1.5 M HCl in EtOAc (20 ml,30.00 mmol) was added and the mixture was stirred at +50° C. for 90 min.The reaction mixture was allowed to assume r.t. while stirring for 30min, the solvents was removed by evaporation. The residual material wastreated with EtOAc (5-10 mL), ether was added (60-70 mL) and the formedslurry was stirred for 30 min at r.t.

The solid HCl salt was collected by filtration and washed with ether,the salt was found to be hygroscopic and was transferred to a desiccatorand dried under reduced pressure at +40° C. Yield 1.68 g (95%)

APCI-MS: m/z 166 [MH⁺—HCl]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.10 (brs, 3H), 7.31-7.02 (m, 4H), 5.98 (d,1H), 4.91 (t, 1H), 3.35 (brs, 1H+ water), 2.31 (s, 3H), 0.93 (d, 3H).

tert-butyl (1R,2S)-1-hydroxy-1-m-tolylpropan-2-ylcarbamate (24c)

The subtitle compound was prepared in two steps analogous to the methodsdescribed in Example 19 (step 19c+19d). Starting from (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (2.323 g, 10 mmol),and m-tolylmagnesium bromide 1.0M solution in THF (12.00 mL, 12.00mmol). Yield 2.33 g (88%)

APCI-MS: m/z 166.1 [MH⁺-BOC]

¹H-NMR (300 MHz, DMSO-d₆): δ 7.22-6.96 (m, 4H), 6.56 (d, 1H), 5.22 (d,1H), 4.49 (t, 1H), 3.56 (m, 1H), 2.29 (s, 3H), 1.32 (s, 9H), 0.92 (d,3H).

Example 25N-[(1R,2S)-1-[4-(ethylsulfanylmethyl)phenyl]-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

(1R,2S)-1-(4-(ethylthiomethyl)phenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-aminehydrochloride (50 mg, 0.11 mmol), 1,1,3,3-tetramethylguanidine (100 μl,0.79 mmol) and ethyl trifluoroacetate (200 μl, 1.68 mmol) in MeOH (2.5mL) was stirred at r.t. for 1 h. The reaction mixture was concentratedby evaporation and the residual material was purified by HPLC. Yield 35mg (62%).

APCI-MS: m/z 532 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 9.49 (d, 1H), 8.17 (d, 1H), 7.73 (m, 2H),7.69 (d, 1H), 7.44-7.24 (m, 6H), 7.19 (dd, 1H), 7.12 (d, 1H), 5.26 (d,1H), 4.24 (m, 1H), 3.68 (s, 2H), 2.31 (q, 2H), 1.33 (d, 3H), 1.09 (t,3H).

(1R,2S)-1-(4-(ethylthiomethyl)phenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-aminehydrochloride (25a)

The subtitle compound was prepared analogous to the method described inExample 19a, starting from(1R,2S)-2-amino-1-(4-(ethylthiomethyl)phenyl)propan-1-ol (225 mg, 1.00mmol). In contrast the reaction mixture was heated at +125° C. for 19 h,after final purification by HPLC the obtained material was dissolved intert-Butyl methyl ether, and precipitated as the hydrochloride salt byadding a solution of 6-7 N HCl in 2-propanol. The obtained material wasfound to contain approximately 5 mol % oxidized material(1R,2S)-1-(4-(ethylsulfinylmethyl)phenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-aminehydrochloride. The material was not repurified. Yield 180 mg (38%).

APCI-MS: m/z 436 [MH⁺—HCl], m/z 452 [MH⁺—HCl] for oxidized impurity.

¹H-NMR (400 MHz, DMSO-d₆): δ 8.38 (brs, 3H), 8.20 (s, 1H), 7.78-7.70 (m,3H), 7.45-7.29 (m, 7H), 7.14 (d, 1H), 5.71 (d, 1H), 3.72 (s, 2H), 3.67(brm, 1H), 2.39 (q, 2H), 1.17 (d, 3H), 1.13 (t, 3H).

(1R,2S)-2-amino-1-(4-(ethylthiomethyl)phenyl)propan-1-ol. (25b)

The subtitle compound was prepared in two steps analogous to the methoddescribed in Example 19 (step 19b+c). Starting from (S)-tert-butyl1-(4-(ethylthiomethyl)phenyl)-1-oxopropan-2-ylcarbamate (750 mg, 2.32mmol). In contrast after final deprotection the obtained hydrochloridesalt was hygroscopic, compound was instead isolated as the free base.Yield 330 mg (63%).

APCI-MS: m/z 226 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 7.32 (m, 4H), 4.48 (d, 1H), 3.73 (s, 2H),3.07 (m, 1H), 2.42 (q, 2H), 1.20 (t, 3H), 1.05 (d, 3H).

(S)-tert-butyl 1-(4-(ethylthiomethyl)phenyl)-1-oxopropan-2-ylcarbamate.(25c)

Magnesium turnings (0.150 g, 6.17 mmol), (4-bromobenzyl)(ethyl)sulfane(1.160 g, 5.02 mmol) and one small crystal of iodine in dry THF (5 mL)was heated to +60° C. for 1 h, the reaction mixture was allowed to reachr.t.

In a separate vessel was placed (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (0.705 g, 3.04 mmol)in dry THF (3 mL), the formed slurry was placed under Argon and cooledon an acetone/ice bath to −10° C. Isopropylmagnesium chloride 2.0Msolution in THF (1.500 mL, 3 mmol) was slowly added, to the formedsolution was thereafter slowly added the previously made Grignardreagent, after addition the mixture was allowed to reach r.t. andstirred for 1.5 h. The reaction mixture was poured into an icecoldmixture of EtOAc (100 mL) and 1M HCl (30 mL) and stirred for a few min.The organic phase was washed with water (30 mL) and brine (30 mL), dried(Na₂SO₄), filtered and evaporated. The residual crude material waspurified by flash chromatography on silica and a gradient of 5% to 30%EtOAc/Heptane. Fractions containing product was combined and solventremoved by evaporation to give the subtitle compound as a colourlesssolid. Yield 750 mg (76%)

APCI-MS: m/z 224.1 [MH⁺-BOC]

¹H-NMR (300 MHz, DMSO-d₆): 7.91 (d, 2H), 7.45 (d, 2H), 7.31 (d, 1H),5.01 (m, 1H), 3.80 (s, 2H), 2.39 (q, 2H), 1.34 (s, 9H), 1.22 (d, 3H),1.15 (t, 3H).

Example 26N-[(1R,2S)-1-[4-(ethylsulfinylmethyl)phenyl]-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

The title compound was formed as a side product during the preparationofN-[(1R,2S)-1-[4-(ethylsulfanylmethyl)phenyl]-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide.Yield 3.4 mg (5.9%)

APCI-MS: m/z 548 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 9.52 (d, 1H), 8.17 (d, 1H), 7.74 (m, 2H),7.69 (d, 1H), 7.44-7.26 (m, 6H), 7.20 (dd, 1H), 7.13 (d, 1H), 5.29 (d,1H), 4.24 (m, 1H), 3.97 (dd, 2H), 2.60 (m, 2H), 1.33 (d, 3H), 1.14 (t,3H).

Example 27N-[(1R,2S)-1-[4-(ethylsulfanylmethyl)phenyl]-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-hydroxy-acetamide

The title compound was prepared analogous to the method described inExample 21 starting from(1R,2S)-1-(4-(ethylthiomethyl)phenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-aminehydrochloride (25a) (50 mg, 0.11 mmol), and acetoxyacetyl chloride (13μL, 0.12 mmol). Yield 33 mg (63%).

APCI-MS: m/z 494.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 8.16 (d, 1H), 7.74 (m, 2H), 7.69 (d, 1H),7.62 (d, 1H), 7.44-7.26 (m, 6H), 7.21 (dd, 1H), 7.10 (d, 1H), 5.52 (brs,1H), 5.40 (d, 1H), 4.24 (m, 1H), 3.72 (dd, 2H), 3.70 (s, 2H), 2.36 (q,2H), 1.17 (d, 3H), 1.11 (t, 3H).

Example 284-Amino-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]butanamide

In a 5 mL Vial, AZ12671597 (60.0 mg, 0.17 mmol),4-(tert-butoxycarbonylamino)butyric acid (33.7 mg, 0.17 mmol),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate(69.3 mg, 0.18 mmol) and triethylamine (0.028 mL, 0.20 mmol) weredissolved in DMF (0.5 mL) and stirred at r.t. over night. Then themixture was diluted with ethyl acetate (30 mL), washed with water andsat. sodium bicarbonate and dried over sodium sulfate. The crude waspurified by flash chromatography on silica gel (ethylacetate/heptane=4:1) and a pale yellow oil (75 mg) was obtained. Theintermediate was dissolved in acetonitrile (5 mL). 6M aq. HCl (1 mL) wasadded and the solution was stirred for 1 h at 50 C. Small impuritieswere removed by purification on reversed phase HPLC. The hygroscopicsalt obtained after freeze drying was taken up with ethyl acetate andwashed with sat. bicarbonate and brine. Removal of the solvent yieldedand freeze drying from acetonitril/water 19 mg (26%).

¹H-NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.67 (d, J=4.6, 2.3 Hz, 2H),7.60 (d, J=9.0 Hz, 1H), 7.44 (d, J=7.3 Hz, 2H), 7.35 (t, J=7.5 Hz, 2H),7.32-7.26 (m, 3H), 7.24 (dd, J=9.2, 2.5 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H),5.34 (d, J=4.6 Hz, 1H), 4.32 (dd, J=6.9, 4.6 Hz, 1H), 2.58 (t, J=7.3 Hz,2H), 2.21 (td, J=7.3, 4.4 Hz, 2H), 1.69 (t, J=7.3 Hz, 2H), 1.24 (d,J=6.9 Hz, 3H).

APCI-MS: m/z 447.2 [MH⁺]

Example 29N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 36 mg, 100 μmol) and acetic anhydride (30 mg, 300 μmol). Yield 37mg (92%).

APCI-MS: m/z 404 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.03 (d, J=0.5 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.2 Hz, 1H), 7.45 (d, J=7.4 Hz, 2H), 7.41-7.26 (m, 5H), 7.23(dd, J=9.1, 2.4 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 5.49 (d, J=3.5 Hz, 1H),4.31 (m, 1H), 1.85 (s, 3H), 1.17 (d, J=6.9 Hz, 3H).

Example 30N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-3-methoxy-propanamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and 3-methoxypropanoyl chloride (18 mg, 150 μmol).Yield 17 mg (74%).

APCI-MS: m/z 448 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.7 Hz, 1H), 7.77 (m, 2H),7.71 (d, J=9.0 Hz, 1H), 7.47 (d, J=7.4 Hz, 2H), 7.39-7.28 (m, 5H), 7.25(dd, J=9.1, 2.4 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 5.49 (d, J=3.5 Hz, 1H),4.33 (m, 1H), 3.53 (m, 2H), 3.18 (s, 3H), 2.36 (t, J=6.3 Hz, 2H), 1.17(d, J=7.1 Hz, 3H).

Example 31N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-methoxy-acetamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and methoxyacetyl chloride (16 mg, 150 μmol). Yield18 mg (86%).

APCI-MS: m/z 434 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.5 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.2 Hz, 1H), 7.48 (d, J=7.3 Hz, 2H), 7.40-7.29 (m, 4H), 7.26(dd, J=9.1, 2.4 Hz, 1H), 7.18 (br. d, J=8.3 Hz, 1H), 7.14 (d, J=2.3 Hz,1H), 5.50 (d, J=4.4 Hz, 1H), 4.41 (m, 1H), 3.76 (dd, J=37.2, 15.0 Hz,2H), 3.28 (s, 3H), 1.24 (d, J=6.9 Hz, 3H).

Example 32N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]benzamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and benzoyl chloride (21 mg, 150 μmol). Yield 19 mg(82%).

APCI-MS: m/z 465 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.02 (d, J=0.7 Hz, 1H), 7.83 (m, 3H),7.75 (m, 2H), 7.68 (d, J=9.2 Hz, 1H), 7.54 (d, J=7.3 Hz, 2H), 7.47 (m,1H), 7.42-7.24 (m, 8H), 7.14 (d, J=2.1 Hz, 1H), 5.64 (d, J=4.1 Hz, 1H),4.57 (m, 1H), 1.36 (d, J=6.9 Hz, 3H).

Example 33N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-phenyl-acetamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and phenylacetyl chloride (23 mg, 150 μmol). Yield22 mg (80%).

APCI-MS: m/z 480 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.03 (d, J=0.7 Hz, 1H), 7.78 (m, 2H),7.69 (d, J=9.2 Hz, 1H), 7.45-7.13 (m, 13H), 7.06 (d, J=2.3 Hz, 1H), 5.46(d, J=3.5 Hz, 1H), 4.32 (m, 1H), 3.47 (dd, J=19.5, 14.3 Hz, 2H), 1.18(d, J=7.1 Hz, 3H).

Example 34[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]carbamoylmethylacetate

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and 2-chloro-2-oxoethyl acetate (20 mg, 150 μmol).Yield 16 mg (70%).

APCI-MS: m/z 462 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.05 (d, J₁=0.7 Hz, 1H), 7.77 (m, 2H),7.71 (d, J=9.0 Hz, 1H), 7.48 (d, J=7.3 Hz, 2H), 7.43-7.28 (m, 5H), 7.25(dd, J=9.1, 2.4 Hz, 1H), 7.14 (d, J=2.3 Hz, 1H), 5.48 (d, J=3.9 Hz, 1H),4.46 (s, 2H), 4.38 (m, 1H), 1.21 (d, J=6.9 Hz, 3H).

Example 35 Methyl[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]carbamoylformate

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and methyl cloro(oxo)acetate (18 mg, 150 μmol).Yield 18 mg (82%).

APCI-MS: m/z 448 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.09 (br.d, J=8.7 Hz, 1H), 8.04 (d, J=0.7Hz, 1H), 7.77 (m, 2H), 7.71 (d, J=9.0 Hz, 1H), 7.49 (d, J=7.3 Hz, 2H),7.42-7.28 (m, 5H), 7.26 (dd, J=9.1, 2.4 Hz, 1H), 7.14 (d, J=2.3 Hz, 1H),5.53 (d, J=4.4 Hz, 1H), 4.39 (m, 1H), 3.76 (s, 3H), 1.32 (d, J=6.9 Hz,3H).

Example 36[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]carbamoylformicacid

Prepared as described in Example 5 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and methyl cloro(oxo)acetate (18 mg, 150 μmol).Yield 19 mg (88%).

APCI-MS: m/z 434 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.21 (br. d, J=8.8 Hz, 1H), 8.03 (s, 1H),7.77 (m, 2H), 7.70 (d, J=9.0 Hz, 1H), 7.50 (d, J=7.3 Hz, 2H), 7.40-7.29(m, 4H), 7.26 (dd, J=9.2, 2.3 Hz, 1H), 7.15 (d, J=2.3 Hz, 1H), 5.53 (d,J=5.0 Hz, 1H), 4.39 (m, 1H), 1.37 (d, J=6.7 Hz, 3H).

Example 37N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-methyl-propanamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and 2-methylpropanoyl chloride (21 mg, 150 μmol).Yield 18 mg (84%).

APCI-MS: m/z 432 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.7 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.2 Hz, 1H), 7.47 (d, J=7.3 Hz, 2H), 7.40-7.26 (m, 5H), 7.24(dd, J=9.2, 2.5 Hz, 1H), 7.17 (br. d, J=7.6 Hz, 1H), 7.11 (d, J=2.3 Hz,1H), 5.47 (d, J=4.2 Hz, 1H), 4.31 (septet, J=6.9 Hz, 1H), 1.20 (d, J=6.9Hz, 3H), 1.02 (d, J=6.7 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H).

Example 382-Chloro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and chloroacetyl chloride (17 mg, 150 μmol). Yield22 mg (73%).

APCI-MS: m/z 438 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.7 Hz, 1H), 7.77 (m, 2H),7.71 (d, J=9.2 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.48 (br. d, J=7.3 Hz,2H), 7.41-7.27 (m, 5H), 7.25 (dd, J=9.1, 2.4 Hz, 1H), 7.13 (d, J=2.3 Hz,1H), 5.51 (d, J=4.1 Hz, 1H), 4.37 (m, 1H), 4.03 (dd, J=17.2, 13.7 Hz,2H), 1.24 (d, J=6.9 Hz, 3H).

Example 392,2-Dichloro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and dichloroacetyl chloride (22 mg, 150 μmol).Yield 20 mg (83%).

APCI-MS: m/z 473 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.5 Hz, 1H), 7.94 (br. d,J=7.8 Hz, 1H), 7.77 (m, 2H), 7.71 (d, J=9.0 Hz, 1H), 7.49 (d, J=7.3 Hz,2H), 7.41-7.27 (m, 5H), 7.25 (dd, J=9.1, 2.4 Hz, 1H), 7.15 (d, J=2.3 Hz,1H), 6.30 (s, 1H), 5.54 (d, J=4.1 Hz, 1H), 4.36 (m, 1H), 1.28 (d, J=6.9Hz, 3H).

Example 402,2,2-Trichloro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and trichloroacetyl chloride (27 mg, 150 μmol).Yield 21 mg (84%).

APCI-MS: m/z 507 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.11 (br. d, J=8.0 Hz, 1H), 8.04 (d,J=0.7 Hz, 1H), 7.76 (m, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.53 (d, J=7.4 Hz,2H), 7.42-7.29 (m, 5H), 7.26 (dd, J=9.1, 2.4 Hz, 1H), 7.18 (d, J=2.3 Hz,1H), 5.55 (d, J=5.3 Hz, 1H), 4.39 (m, 1H), 1.41 (d, J=6.9 Hz, 3H).

Example 41N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]butanamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and butanoyl chloride (16 mg, 150 μmol). Yield 18mg (82%).

APCI-MS: m/z 432 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.03 (d, J=0.7 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.2 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.38-7.25 (m, 5H), 7.23(dd, J=9.1, 2.4 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 5.49 (d, J=3.9 Hz, 1H),4.33 (m, 1H), 2.09 (td, J=7.4, 2.8 Hz, 2H), 1.53 (sextet, J=7.3 Hz, 2H),1.19 (d, J=6.9 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H).

Example 42N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and 2,2-dimethylpropanoyl chloride (18 mg, 150μmol). Yield 17 mg (74%).

APCI-MS: m/z 446 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.7 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.0 Hz, 1H), 7.48 (d, J=7.4 Hz, 2H), 7.38-7.26 (m, 5H), 7.25(dd, J=9.1, 2.4 Hz, 1H), 7.13 (d, J=2.1 Hz, 1H), 6.78 (br. d, J=8.3 Hz,1H), 5.46 (d, J=5.0 Hz, 1H), 4.34 (m, 1H), 1.23 (d, J=6.9 Hz, 3H), 1.05(s, 9H).

Example 43N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]cyclobutanecarboxamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and cyclobutanecarbonyl chloride (18 mg, 150 μmol).Yield 18 mg (82%).

APCI-MS: m/z 444 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.03 (d, J=0.5 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.2 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.39-7.25 (m, 5H), 7.22(dd, J=9.1, 2.4 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 7.09 (br. d, J=8.9 Hz,1H), 5.47 (d, J=4.1 Hz, 1H), 4.32 (m, 1H), 3.03 (quintet, J=8.2 Hz, 1H),2.21 (m, 1H), 2.13-1.68 (m, 5H, partially covered with the signal ofsolvent), 1.18 (d, J=6.9 Hz, 3H).

Example 442,2-Difluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and difluoroacetyl chloride (23 mg, 150 μmol).Yield 21 mg (95%).

APCI-MS: m/z 440 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.08 (br. d, J=7.8 Hz, 1H), 8.03 (d,J=0.7 Hz, 1H), 7.77 (m, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.49 (d, J=7.3 Hz,2H), 7.40-7.27 (m, 5H), 7.24 (dd, J=9.2, 2.5 Hz, 1H), 7.13 (d, J=2.3 Hz,1H), 6.06 (t, J=54.0 Hz, 1H), 5.51 (d, J=4.4 Hz, 1H), 4.41 (m, 1H), 1.31(d, J=6.9 Hz, 3H).

Example 452-Fluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 36 mg, 100 μmol) and difluoroacetyl chloride (29 mg, 300 μmol).Yield 40 mg (95%).

APCI-MS: m/z 422 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (s, 1H), 7.77 (m, 2H), 7.71 (d,J=9.2 Hz, 1H), 7.48 (d, J=7.3 Hz, 2H), 7.44 (br. d, J=7.6 Hz, 1H),7.41-7.28 (m, 5H), 7.25 (dd, J=9.1, 2.4 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H),5.50 (d, J=4.4 Hz, 1H), 4.78 (q, J=14.0 Hz, 1H), 4.66 (q, J=14.0 Hz,1H), 4.44 (m, 1H), 1.29 (d, J=6.9 Hz, 3H).

Example 46N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Prepared as described in Example 1 using(1R,2S)-1-(4-ethylphenyl)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}propan-2-amine(7a, 39 mg, 100 μmol) and trifluoroacetic anhydride (63 mg, 300 μmol).Yield 44 mg (90%).

APCI-MS: m/z 484 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.59 (br. d, J=7.8 Hz, 1H), 8.04 (s, 1H),7.77 (m, 2H), 7.70 (d, J=9.0 Hz, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.33 (m,2H), 7.23 (m, 3H), 7.15 (d, J=2.3 Hz, 1H), 5.49 (d, J=4.6 Hz, 1H), 4.41(m, 1H), 2.62 (q, J=7.6 Hz, 2H), 1.37 (d, J=6.9 Hz, 3H), 1.18 (t, J=7.6Hz, 3H).

Example 472-Chloro-2-fluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide

Prepared as described in Example 1 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and chlorofluoroacetyl chloride (19 mg, 150 μmol).Yield 16 mg (70%).

APCI-MS: m/z 456 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (s, 1H), 7.98 (br. t, J=7.1 Hz, 1H),7.77 (m, 2H), 7.71 (d, J=9.0 Hz, 1H), 7.49 (dd, J=7.4, 2.8 Hz, 2H),7.41-7.27 (m, 5H), 7.25 (dt, J=9.1, 2.2 Hz, 1H), 7.14 (dd, J=5.1, 2.3Hz, 1H), 6.55 (dd, J=50.0, 9.8 Hz, 1H), 5.52 (dd, J=7.3, 4.4 Hz, 1H),4.39 (m, 1H), 1.31 (dd, J=6.9, 2.7 Hz, 3H).

Example 48(2S)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-hydroxy-propanamide

Prepared as described in Example 5 using(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(1a, 18 mg, 50 μmol) and methyl (1S)-2-chloro-1methyl-2-oxoethyl acetate(22 mg, 150 μmol). Yield 20 mg (91%).

APCI-MS: m/z 434 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.7 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.2 Hz, 1H), 7.48 (d, J=7.3 Hz, 2H), 7.40-7.28 (m, 5H), 7.25(dd, J=9.2, 2.5 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 5.49 (d, J=4.1 Hz, 1H),4.35 (m, 1H), 4.06 (q, J=6.8 Hz, 1H), 1.25 (d, J=6.7 Hz, 3H), 1.22 (d,J=6.9 Hz, 3H).

Example 492,2,2-Trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-hydroxyphenyl)propan-2-yl]acetamide

To a stirred solution of2,2,2-trifluoro-N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)acetamide(Example 6, 10 mg, 20 μmol) in methylbenzene (1 ml) was addeddodecanethiole (1 ml), followed with anhydrous aluminum chloride (5.3mg, 40 μmol). The mixture was stirred at 40° C. for 1 h. Methylbenzenewas removed in vacuo, the solution in dodecanethiole was diluted withn-heptane (10 ml). Oily precipitate has formed, which was washed withheptane, dried in vacuo, and dissolved in acetonitrile/water mixture.The crude product was purified by preparative HPLC afforded 4 mg ofproduct as a white solid (42%).

APCI-MS: m/z 474 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.60 (d, J=8.0 Hz, 1H), 8.06 (d, J=0.5Hz, 1H), 7.77 (m, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.34 (m, 2H), 7.23 (dd,J=6.9, 2.1 Hz, 1H), 7.19 (m, 1H), 7.14 (d, J=2.1 Hz, 1H), 6.95 (m, 2H),6.77 (dd, J=8.0, 1.5 Hz, 1H), 5.44 (d, J=4.6 Hz, 1H), 4.41 (m, 1H), 1.37(d, J=6.9 Hz, 3H).

Example 50N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-fluoro-acetamide

Prepared as described in Example 1 using(1R,2S)-1-(4-ethylphenyl)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}propan-2-amine(7a, 20 mg, 50 μmol) and fluoroacetyl chloride (14 mg, 150 μmol). Yield15 mg (65%).

APCI-MS: m/z 450 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.5 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.2 Hz, 1H), 7.44-7.30 (m, 4H), 7.23 (m, 3H), 7.13 (d, J=2.3Hz, 1H), 5.48 (d, J=4.2 Hz, 1H), 4.78 (dd, J=26.4, 14.0 Hz, 1H), 4.67(dd, J=26.4, 14.0 Hz, 1H), 4.42 (m, 1H), 2.62 (q, J=7.6 Hz, 2H), 1.28(d, J=6.9 Hz, 3H), 1.19 (t, J=7.6 Hz, 3H).

Example 51N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide

Prepared as described in Example 1 using(1R,2S)-1-(4-ethylphenyl)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}propan-2-amine(7a, 20 mg, 50 μmol) and 2-methylpropanoyl chloride (16 mg, 150 nmol).Yield 18 mg (78%).

APCI-MS: m/z 460 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.7 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.0 Hz, 1H), 7.39-7.30 (m, 4H), 7.22 (m, 3H), 7.15 (br. d,J=8.1 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 5.44 (d, J=4.1 Hz, 1H), 4.29 (m,1H), 2.61 (q, J=7.6 Hz, 2H), 2.37 (septet, J=6.9 Hz, 1H), 1.18 (m, 6H),1.02 (d, J=6.9 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H).

Example 52N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 1 using(1R,2S)-1-(4-ethylphenyl)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}propan-2-amine(7a, 20 mg, 50 μmol) and 2,2-dimethylpropanoyl chloride (18 mg, 150μmol). Yield 17 mg (71%)

APCI-MS: m/z 474 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (s, 1H), 7.77 (m, 2H), 7.69 (d,J=9.2 Hz, 1H), 7.40-7.30 (m, 4H), 7.24 (dd, J=9.1, 2.4 Hz, 1H), 7.21 (d,J=8.1 Hz, 2H), 7.14 (d, J=2.1 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 5.42 (d,J=4.8 Hz, 1H), 4.33 (m, 1H), 2.61 (q, J=7.5 Hz, 2H), 1.22 (d, J=6.7 Hz,3H), 1.18 (t, J=7.6 Hz, 3H), 1.05 (s, 9H).

Example 532-Fluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]acetamide

Prepared as described in Example 1 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a, 19 mg, 50 μmol) and fluoroacetyl chloride (14 mg, 150 μmol). Yield16 mg (71%).

APCI-MS: m/z 452 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.05 (d, J=0.9 Hz, 1H), 7.77 (m, 1H),7.71 (d, J=9.2 Hz, 1H), 7.42 (br. d, J=8.7 Hz, 1H), 7.37-7.23 (m, 3H),7.15 (d, J=2.1 Hz, 1H), 7.05 (d, J=7.4 Hz, 2H), 6.86 (m, 1H), 5.47 (d,J=4.2 Hz, 1H), 4.79 (dd, J=26.3, 13.9 Hz, 1H), 4.67 (dd, J=26.3, 13.9Hz, 1H), 4.44 (m, 1H), 3.78 (s, 3H), 1.30 (d, J=6.9 Hz, 3H).

Example 54N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-methoxy-acetamide

Prepared as described in Example 1 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a, 19 mg, 50 μmol) and methoxyacetyl chloride (16 mg, 150 μmol). Yield23 mg (99%).

APCI-MS: m/z 464 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.05 (d, J=0.7 Hz, 1H), 7.78 (m, 2H),7.71 (d, J=9.2 Hz, 1H), 7.37-7.24 (m, 4H), 7.16 (d, J=2.3 Hz, 1H), 7.14(br. d, J=9.5 Hz, 1H), 7.05 (m, 2H), 6.85 (dd, J=8.2, 1.7 Hz, 1H), 5.47(d, J=4.2 Hz, 1H), 4.41 (m, 1H), 3.78 (s, 3H), 3.76 (q, J=17.1 Hz, 2H),3.29 (s, 3H), 1.25 (d, J=6.9 Hz, 3H).

Example 55N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-methyl-propanamide

Prepared as described in Example 1 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a, 19 mg, 50 μmol) and 2-methylpropanoyl chloride (16 mg, 150 μmol).Yield 17 mg (74%).

APCI-MS: m/z 462 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.05 (d, J=0.7 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.2 Hz, 1H), 7.37-7.25 (m, 3H), 7.24 (dd, J=9.1, 2.4 Hz, 1H),7.16 (br. d, J=7.8 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 7.03 (m, 2H), 6.84(m, 1H), 5.44 (d, J=4.1 Hz, 1H), 4.31 (m, 1H), 3.78 (s, 3H), 2.38(septet, J=6.8 Hz, 1H), 1.20 (d, J=6.9 Hz, 3H), 1.02 (d, J=6.7 Hz, 3H),0.93 (d, J=6.9 Hz, 3H).

Example 56N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]cyclopentanecarboxamide

To a stirred solution of 1,1-carbonyldiimidazole (12 mg, 70 μmol) indichloromethane (1 ml) was added cyclopentanecarboxylic acid (11 μl, 100μmol) to give a colorless solution. The reaction mixture was stirred for1 h at r.t. Then a solution of(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a, 19 mg, 50 μmol) in dichloromethane (0.5 ml) was added, and thestirring was continued at r.t. overnight. The solvent was removed invacuo, the residue dissolved in acetonitrile/water mixture, and thecrude product purified by preparative HPLC. Yield 18 mg (76%).

APCI-MS: m/z 488 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.05 (s, 1H), 7.77 (m, 2H), 7.70 (d,J=9.2 Hz, 1H), 7.38-7.21 (m, 4H), 7.19 (br. d, J=8.1 Hz, 1H), 7.13 (d,J=2.3 Hz, 1H), 7.03 (m, 2H), 6.84 (m, 1H), 5.45 (d, J=4.1 Hz, 1H), 4.32(m, 1H), 3.78 (s, 3H), 2.59 (quintet, J=7.7 Hz, 1H), 1.78-1.40 (m, 8H),1.20 (d, J=6.9 Hz, 3H).

Example 57(2R)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-hydroxy-propanamide

To a stirred solution of 1,1-carbonyldiimidazole (31 mg, 190 Amok) inTHF (1 ml) was added (2R)-2-hydroxypropanoic acid (18 mg, 20 μmol) togive a colorless solution. The reaction mixture was stirred for 1 h atr.t. Then a solution of(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a, 39 mg, 100 μmol) in THF (0.5 ml) was added, and the stirring wascontinued at r.t. overnight. The solvent was removed in vacuo, theresidue dissolved in acetonitrile/water mixture, and the crude productpurified by preparative HPLC. Yield 16 mg (35%).

APCI-MS: m/z 464 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.05 (d, J=0.5 Hz, 1H), 7.77 (m, 2H),7.71 (d, J=9.2 Hz, 1H), 7.38-7.23 (m, 4H), 7.16 (d, J=2.3 Hz, 1H), 7.05(m, 2H), 6.85 (dd, J=8.2, 1.9 Hz, 1H), 5.45 (d, J=4.4 Hz, 1H), 4.37 (m,1H), 4.07 (q, J=6.8 Hz, 1H), 3.78 (s, 3H), 1.24 (d, J=6.9 Hz, 3H), 1.18(d, J=6.9 Hz, 3H).

Example 58(2S)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-hydroxy-propanamide

Prepared as described in Example 110 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a, 39 mg, 1000 μmol) and (2S)-2-hydroxypropanoic acid (18 mg, 20μmol). Yield 17 mg (37%).

APCI-MS: m/z 464 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.05 (d, J=0.5 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.2 Hz, 1H), 7.39-7.23 (m, 4H), 7.15 (d, J=2.3 Hz, 1H), 7.04(m, 2H), 6.85 (m, 1H), 5.46 (d, J=4.1 Hz, 1H), 4.36 (m, 1H), 4.06 (q,J=6.7 Hz, 1H), 3.78 (s, 3H), 1.26 (d, J=6.7 Hz, 3H), 1.23 (d, J=6.9 Hz,3H).

Example 59N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-[4-(trifluoromethyl)phenyl]propan-2-yl]-2-methoxy-acetamide

Prepared as described in Example 1 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine(59a, 21 mg, 50 μmol) and methoxyacetyl chloride (16 mg, 150 μmol).Yield 17 mg (69%).

APCI-MS: m/z 502 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.05 (d, J=0.5 Hz, 1H), 7.70-7.80 (m,6H), 7.34 (m, 2H), 7.28 (dd, J=9.2, 2.5 Hz, 1H), 7.25 (br. d, J=8.5 Hz,1H), 7.17 (d, J=2.3 Hz, 1H), 5.61 (d, J=4.8 Hz, 1H), 4.44 (m, 1H), 3.80(d, J=15.0 Hz, 1H), 3.70 (d, J=15.0 Hz, 1H), 3.28 (s, 3H), 1.28 (d,J=6.9 Hz, 3H).

(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine(59a)

Prepared as described in Example 6 (step 6a), using(1R,2S)-2-amino-1-[4-(trifluoromethyl)phenyl]propan-1-ol (136 mg, 0.62mmol). Yield 70 mg (32%).

APCI-MS: m/z 430 [MH⁺]

¹H NMR (400 MHz, d₆-DMSO+D₂O, TFA added) δ 8.18 (s, 1H), 7.69-7.81 (m,3H), 7.65 (d, J=8.1 Hz, 2H), 7.39 (t, J=8.8 Hz, 2H), 7.32 (dd, J=9.2,2.3 Hz, 1H), 7.15 (d, J=2.1 Hz, 1H), 5.77 (d, J=2.7 Hz, 1H), 3.78 (m,1H), 1.16 (d, J=6.9 Hz, 3H).

(1R,2S)-2-amino-1-[4-(trifluoromethyl)phenyl]propan-1-ol (59b)

Prepared from tert-butyl{(1S,2R)-2-hydroxy-1-methyl-2-[4-(trifluoromethyl)phenyl]ethyl}carbamate(59c, 279 mg, 0.87 mmol) as described in Example 7, Step 7b. Yield 175mg (91%).

APCI-MS: m/z 220 [MH⁺]

¹H NMR (400 MHz, d₆-DMSO) δ 7.66 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz,2H), 5.36 (s, 1H), 4.43 (s, 1H), 2.92 (dd, J=6.5, 5.0 Hz, 1H), 1.39 (s,2H), 0.83 (d, J=6.4 Hz, 3H).

tert-Butyl{(1S,2R)-2-hydroxy-1-methyl-2-[4-(trifluoromethyl)phenyl]ethyl}carbamate(59c)

Prepared from tert-butyl{(1S)-1-methyl-2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl}carbamate (58c,385 mg, 1.21 mmol) as described in Example 7, Step 7c. Yield 279 mg(72%).

¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.5 Hz,2H), 4.93 (s, 1H), 4.56 (br.s, 1H), 4.04 (br.s, 1H), 3.52 (br.s, 1H),1.48 (s, 9H), 1.00 (d, J=6.9 Hz, 3H).

tert-Butyl{(1S)-1-methyl-2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl}carbamate (59c)

To a stirred mixture of isopropylmagnesium chloride-lithium chloridecomplex (14% wt 1 M solution, 726 mg, 5 mmol, 5 ml) and THF (5 ml) wasadded 1-bromo-4-(trifluoromethyl)benzene (1.125 g, 5 mmol) under argon.The stirring was continued at r.t. for 4 h. A solution ofN²-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-alaninamide (232 mg, 1mmol) in THF (10 ml) was added dropwise, and the stirring was continuedovernight at r.t. Then the reaction mixture was quenched with sat. aq.NH₄Cl (20 ml), and stirring was continued for 30 min. The layers wereseparated, the aqueous layer extracted with ethyl acetate (20 ml). Thecombined organic extracts were dried over Na₂SO₄, and the solvent wasevaporated to give yellow partly crystalline product. Purification byflash chromatography on silica gel with n-heptane/ethyl acetate affordedcolourless solid, 260 mg (82%).

¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.1 Hz,2H), 5.46 (d, J=7.1 Hz, 1H), 5.29 (quintet, J=7.2 Hz, 1H), 1.46 (s, 9H),1.41 (d, J=7.1 Hz, 3H).

Example 60N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-[4-(trifluoromethyl)phenyl]propan-2-yl]-2-hydroxy-acetamide

Prepared as described in Example 5 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine(59a, 21 mg, 50 μmol) and 2-chloro-2-oxoethyl acetate (21 mg, 150 μmol).Yield 18 mg (76%).

APCI-MS: m/z 488 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.7 Hz, 1H), 7.70-7.80 (m,6H), 7.43 (d, J=8.7 Hz, 1H), 7.34 (m, 2H), 7.28 (dd, J=9.2, 2.5 Hz, 1H),7.17 (d, J=2.3 Hz, 1H), 5.62 (d, J=4.2 Hz, 1H), 4.44 (m, 1H), 3.90 (dd,J=21.0, 15.8 Hz, 2H), 1.27 (d, J=6.9 Hz, 3H).

Example 61N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-[4-(trifluoromethyl)phenyl]propan-2-yl]propanamide

Prepared as described in Example 1 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine(59a, 21 mg, 50 μmol) and propanoyl chloride (14 mg, 150 μmol). Yield 17mg (72%).

APCI-MS: m/z 486 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.7 Hz, 1H), 7.68-7.80 (m,6H), 7.34 (m, 2H), 7.30 (d, J=8.3 Hz, 1H), 7.25 (dd, J=9.1, 2.4 Hz, 1H),7.14 (d, J=2.3 Hz, 1H), 5.58 (d, J=4.1 Hz, 1H), 4.35 (m, 1H), 2.12 (m,2H), 1.21 (d, J=6.9 Hz, 3H), 0.98 (t, J=7.6 Hz, 3H).

Example 622,2,2-Trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-phenyl-propan-2-yl]acetamide

Prepared as described in Example 1 using(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-phenyl-propan-2-amine(50 mg, 0.13 mmol) and trifluoroacetic anhydride (0.075 mL, 0.53 mmol).Yield 54 mg (86%).

APCI-MS: m/z 472.3 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 7.91 (s, 1H), 7.66 (m, 2H), 7.49 (s, 1H),7.44-7.40 (m, 2H), 7.35 (m, 2H), 7.32-7.26 (m, 3H), 6.89 (s, 1H), 5.41(d, J=5.5 Hz, 1H), 4.44 (m, 1H), 2.51 (s, 3H), 1.40 (d, J=6.9 Hz, 3H).

(1R,2S)-1-[1-(4-Fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-phenyl-propan-2-amine(62a)

Prepared as described in Example 1 from(1R,2S)-2-amino-1-phenylpropan-1-ol (257 mg, 1.70 mmol), and1-(4-fluorophenyl)-5-iodo-6-methylindazole (200 mg, 0.57 mmol). Yield169 mg (79%).

¹H-NMR (400 MHz, CD₃OD): δ 7.90 (s, 1H), 7.65 (m, 2H), 7.49 (s, 1H),7.43-7.33 (m, 4H), 7.29 (m, 3H), 6.91 (s, 1H), 5.23 (d, J=4.8 Hz, 1H),2.51 (s, 3H), 1.22 (d, J=6.5 Hz, 3H).

1-(4-Fluorophenyl)-5-iodo-6-methylindazole (62b)

5-Iodo-6-methylindazole (1.3 g, 5.0 mmol), p-fluorobenzeneboronic acid(1.4 g, 10 mmol), anhydrous copper(II) acetate (1.4 g, 7.5 mmol) andpyridine (0.80 mL, 10 mmol) were stirred in dichloromethane (30 mL)overnight. Additional portions of p-fluorobenzeneboronic acid (0.47 g,3.4 mmol), anhydrous copper(II) acetate (0.45 g, 2.5 mmol) and pyridine(0.27 mL, 3.4 mmol) were added. The mixture was filtered through celiteafter stirring for an additional night. The filtrate was concentratedand purified by column chromatography (SiO₂, toluene) to give thesubtitle compound (0.90 g, 51%) as a light orange powder.

APCI-MS: m/z 353.1 [MH⁺]

¹H-NMR (400 MHz, CD₂Cl₂): δ 8.29 (s, 1H), 8.06 (s, 1H), 7.66 (m, 2H),7.61 (s, 1H), 7.26 (m, 2H), 2.57 (s, 3H).

5-Iodo-6-methylindazole (62c)

1-Acetyl-5-iodo-6-methylindazole (1.5 g, 5.0 mmol) was stirred withammonia (7 M in methanol, 4 mL) in methano/THF (2/1, 15 mL) for 1 h. Thesolution was evaporated to give the subtitle compound (1.3 g, 100%) asan off-white powder.

APCI-MS: m/z 259.1 [MH⁺]

1-Acetyl-5-iodo-6-methylindazole (62d)

Acetic acid anhydride (6.9 mL, 72 mmol) was added to a slurry of2,5-dimethyl-4-indoaniline (6.0 g, 24 mmol) and potassium acetate (2.4g, 24 mmol) in benzene (50 mL). The mixture was heated to 80° C. andisopentylnitrit (4.8 mL, 36 mmol) was added during 20 min. The mixturewas stirred at 80° C. overnight, then cooled and filtered. The filtratewas evaporated and purified by column chromatography (SiO₂,dichloromethane). Product containing fractions were pooled andconcentrated. The subtitle compound (1.5 g, 21%) was obtained ascrystals from ethyl acetate.

¹H-NMR (400 MHz, CD₂Cl₂): δ 8.37 (s, 1H), 8.24 (s, 1H), 8.02 (s, 1H),2.73 (s, 3H), 2.61 (s, 3H).

Example 63N-[(1R,2S)-1-[1-(4-Fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 1 using(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-phenyl-propan-2-amine(50 mg, 0.13 mmol) and pivaloyl chloride (0.065 mL, 0.53 mmol). Yield 53mg (87%).

APCI-MS: m/z 460.4 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 7.92 (s, 1H), 7.66 (m, 2H), 7.49 (s, 1H),7.46-7.42 (m, 2H), 7.37-7.20 (m, 5H), 6.90 (s, 1H), 5.39 (d, J=5.7 Hz,1H), 4.41 (m, 1H), 2.52 (s, 3H), 1.32 (d, J=6.9 Hz, 3H), 1.04 (s, 9H).

Example 64N-[(1R,2S)-1-[1-(4-Fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-phenyl-propan-2-yl]-2-hydroxy-acetamide

Acetoxyacetyl chloride (0.071 mL, 0.66 mmol) was added to a solution of(1R,2S)-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yloxy)-1-phenylpropan-2-amine(62 mg, 0.17 mmol) and triethylamine (0.18 mL, 1.3 mmol) in THF (2.5 mL)at r.t. The mixture was stirred overnight and concentrated. The residuewas dissolved in methanol (2 mL) and 28% ammonia (2 mL) and stirred atr.t. overnight. The title compound (57 mg, 80%) was obtained afterpurification by semi-preparative HPLC.

APCI-MS: m/z 434.3-[MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 7.90 (s, 1H), 7.66 (m, 2H), 7.51 (s, 1H),7.45-7.41 (m, 2H), 7.37 (m, 2H), 7.33-7.26 (m, 3H), 6.86 (s, 1H), 5.46(d, J=4.3 Hz, 1H), 4.46 (m, 1H), 3.93 (m, 2H), 2.53 (s, 3H), 1.27 (d,J=6.9 Hz, 3H).

Example 652,2,2-Trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]acetamide

Prepared as described in Example 1 using(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine(73 mg, 0.18 mmol) and trifluoroacetic anhydride (0.102 ml, 0.72 mmol).Yield 69 mg (76%).

APCI-MS: m/z 502.4 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 7.93 (s, 1H), 7.66 (m, 2H), 7.49 (s, 1H),7.33-7.23 (m, 3H), 7.02-6.95 (m, 2H), 6.91 (s, 1H), 6.85 (dd, J₁=8.1 Hz,J₂=2.3 Hz, 1H), 5.37 (d, J=5.5 Hz, 1H), 4.44 (m, 1H), 3.77 (s, 3H), 2.51(s, 3H), 1.40 (d, J=6.9 Hz, 3H).

(1R,2S)-1-[1-(4-Fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine(65a)

Prepared as described in Example 1 from(1R,2S)-1-hydroxy-1-(3-methoxyphenyl)propan-2-ammonium chloride (185 mg,0.85 mmol) and 1-(4-fluorophenyl)-5-iodo-6-methylindazole (300 mg, 0.85mmol). Yield 224 mg (65%).

¹H-NMR (400 MHz, CD₃OD): δ 7.92 (s, 1H), 7.66 (m, 2H), 7.49 (s, 1H),7.33-7.25 (m, 3H), 7.01-6.95 (m, 2H), 6.93 (s, 1H), 6.85 (dd, J=7.8 Hz,J₂=2.1 Hz, 1H), 5.18 (d, J=5.0 Hz, 1H), 3.77 (s, 3H), 2.51 (s, 3H), 1.23(d, J=6.5 Hz, 3H).

Example 66N-[(1R,2S)-1-[1-(4-Fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 1 using(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine(73 mg, 0.18 mmol) and pivaloyl chloride (0.088 ml, 0.72 mmol). Yield 75mg (85%).

APCI-MS: m/z 490.4 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 7.93 (s, 1H), 7.66 (m, 2H), 7.49 (s, 1H),7.32-7.22 (m, 3H), 7.03-6.98 (m, 2H), 6.92 (s, 1H), 6.83 (dd, J=8.5 Hz,J₂=2.1 Hz, 1H), 5.35 (d, J=5.7 Hz, 1H), 4.40 (m, 1H), 3.77 (s, 3H), 2.52(s, 3H), 1.32 (d, J=6.9 Hz, 3H), 1.06 (s, 9H).

Example 67N-[(1R,2S)-1-[1-(4-Fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-hydroxy-acetamide

Prepared as described in Example 102 using(1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine(73 mg, 0.18 mmol) and acetoxyacetyl chloride (0.077 ml, 0.72 mmol).Yield 67 mg (80%).

APCI-MS: m/z 464.3 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 7.92 (s, 1H), 7.67 (m, 2H), 7.50 (s, 1H),7.33-7.25 (m, 3H), 7.03-6.97 (m, 2H), 6.89-6.84 (m, 2H), 5.43 (d, J=4.2Hz, 1H), 4.46 (m, 1H), 3.93 (m, 2H), 3.77 (s, 3H), 2.53 (s, 3H), 1.27(d, J=6.9 Hz, 3H).

Example 682,2,2-Trifluoro-N-[(2S*,3S*)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenoxy-butan-2-yl]acetamide

The racemate was prepared as described in Example 1 using(2RS,3RS)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenoxy-butan-2-amine(0.13 g, 0.33 mmol) and trifluoroacetic anhydride (0.14 ml, 1.0 mmol).Yield 155 mg (96%). The two enantiomers were separated bysemi-preparative HPLC (ChiralpakIA, 21×250 mm, 5 μm, 20%isopropanole/80% iso-hexane). Yield of the faster eluting compound was57 mg.

APCI-MS: m/z 488.3 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.14 (s, 1H), 7.71 (m, 2H), 7.64 (d, J=9.0Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.32 (m, 2H), 7.28-7.23 (m, 3H),6.96-6.89 (m, 3H), 4.79 (m, 1H), 4.51 (m, 1H), 4.24 (m, 2H), 1.43 (d,J=6.9 Hz, 3H).

(2RS, 3RS)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenoxy-butan-2-amine(68a)

Prepared as described in Example 1 from(2RS,3RS)-3-amino-1-phenoxy-butan-2-ol (250 mg, 1.37 mmol), and1-(4-fluorophenyl)-5-iodoindazole (557 mg, 1.64 mmol). Yield 157 mg (29

¹H-NMR (400 MHz, CD₃OD): δ 8.14 (s, 1H), 7.71 (m, 2H), 7.64 (d, J=9.0Hz, 1H), 7.46 (m, 1H), 7.35-7.21 (m, 5H), 6.95-6.88 (m, 3H), 4.59 (m,1H), 4.28 (m, 2H), 3.41 (m, 1H), 1.29 (d, J=6.7 Hz, 3H).

(2RS,3RS)-3-Amino-1-phenoxy-butan-2-ol (68b)

3-Nitro-1-phenoxy-butan-2-ol (1.7 g, 8.0 mmol) in methanol (50 mL) washydrogenated over platinum oxide (300 mg) at atmospheric pressureovernight. The mixture was filtered through celite and purified bysemi-preparative HPLC (XBridge, C18, 5 μm, 19×50 mm, 12 min gradient of5-20% acetonitrile in (water+2 mL NH3/L). Fractions containing thefaster eluting peak were pooled and concentrated to give the subtitlecompound (409 mg).

¹H-NMR (400 MHz, CD₃OD): δ 7.26 (m, 2H), 6.98-6.89 (m, 3H), 4.01 (m,2H), 3.80 (m, 1H), 3.07 (m, 1H), 1.15 (d, J=6.5 Hz, 3H). The couplingconstant between the methine protons was measured to 4.95 Hz. Comparisonwith the coupling constant of norephedrine, with known stereochemistry,indicated that the first eluting racemate has the(2R,3R)/(2S,3S)-configuration and the secondly eluting racemate has the(2R,3S)/(2S,3R)-configuration.

3-Nitro-1-phenoxy-butan-2-ol (68c)

Synthesized analogously to the method described by P. B. Kisanga and J.G. Verkade, J. Org. Chem., 64, 4298-4303 (1999).

2-Phenoxyacetaldehyde (1.36 g, 10 mmol) was added to a suspension ofanhydrous magnesium sulfate (2.65 g, 22 mmol) in nitroethane (7.0 mL)under an argon atmosphere. After 5 min a solution of2,8,9-triisopropyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane(0.30 g, 1.0 mmol) in nitromethane (3.0 mL) was added. The mixture wasvigorously stirred for 5 days at r.t., filtered through celite andconcentrated. Purification by column chromatography (SiO₂,dichloromethane/t-butyl methyl ether) gave the subtitle compound as anoil (1.7 g, 81%).

¹H-NMR (400 MHz, CDCl₃): δ 7.32 (m, 2H), 7.02 (m, 1H), 6.92 (m, 2H),4.92 (m, 0.6H), 4.84 (m, 0.4H), 4.6 (m, 0.4H), 4.33 (m, 0.6H), 4.17 (m,0.6H), 4.12-4.06 (m, 1H), 4.01 (m, 0.4H), 2.78 (d, J=7.6 Hz, 0.6H), 2.70(d, J=5.3 Hz, 0.4H), 1.68 (d, J=6.9 Hz, 1.2H), 1.63 (d, J=6.9 Hz, 1.8H).

2-Phenoxyacetaldehyde (68d)

Synthesized analogously to the method described by M. Daumas et al,Synthesis, 64-65 (1989).

Sodium periodate (0.65 M in water, 20 mL) was added to a vigorouslystirred suspension of silica gel (20 g) in dichloromethane (160 mL),followed by a solution of 3-phenoxy-1,2-propanediol (1.68 g, 10.0 mmol)in dichloromethane (20 mL). After stirring for 10 min the mixture wasfiltered and the filtrate was concentrated to give the subtitle compound(1.36 g, 100%).

¹H-NMR (400 MHz, CDCl₃): δ 9.89 (s, 1H9, 7.33 (m, 2H), 7.04 (m, 1H),6.92 (m, 2H), 4.59 (s, 2H).

Example 692,2,2-trifluoro-N-[2R*,3R*-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenoxy-butan-2-yl]acetamide

Obtained as the slower eluting compound (49 mg) in the chiral separationin Example 68.

APCI-MS: m/z 488.3 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.13 (s, 1H), 7.71 (m, 2H), 7.64 (d, J=9.2Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.31 (m, 2H), 7.28-7.22 (m, 3H),6.96-6.89 (m, 3H), 4.79 (m, 1H), 4.51 (m, 1H), 4.24 (m, 2H), 1.43 (d,J=7.1, 3H).

Example 702,2,2-Trifluoro-N-[(2RS,3SR)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenoxy-butan-2-yl]acetamide

Prepared as described in Example 1 using(2RS,3SR)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenoxy-butan-2-amine(38 mg, 0.097 mmol) and trifluoroacetic anhydride (0.041 ml, 0.29 mmol).Yield 40 mg (85%).

APCI-MS: m/z 488.3 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.15 (s, 1H), 7.71 (m, 2H), 7.64 (d, J=9.2Hz, 1H), 7.50 (d, J=2.3 Hz, 1H), 7.35-7.22 (m, 5H), 6.96-6.89 (m, 3H),4.76 (m, 1H), 4.60 (m, 1H), 4.29 (m, 1H), 4.21 (m, 1H), 1.39 (d, J=6.9,3H).

(2RS,3SR)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenoxy-butan-2-amine(70a)

Prepared as described in Example 1 from(2RS,3SR)-3-amino-1-phenoxy-butan-2-ol (319 mg, 1.75 mmol), and1-(4-fluorophenyl)-5-iodoindazole (710 mg, 2.10 mmol). Yield 244 mg(36%).

¹H-NMR (400 MHz, CD₂Cl2): δ 8.06 (s, 1H), 7.67 (m, 2H), 7.59 (d, J=9.2Hz, 1H), 7.37 (d, J=2.1 Hz, 1H), 7.30-7.20 (m, 5H), 6.97-6.88 (m, 3H),4.39 (m, 1H), 4.29 (m, 1H), 4.19 (m, 1H), 3.43 (m, 1H), 1.25 (d, J=6.6Hz, 3H).

(2RS,3SR)-3-Amino-1-phenoxy-butan-2-ol (70b)

The subtitle compound (319 mg) was obtained as the secondly eluting peakin the chromatographic purification in Example 68b.

¹H-NMR (400 MHz, CD₃OD): δ 7.27 (m, 2H), 6.98-6.89 (m, 3H), 4.02 (m,2H), 3.67 (m, 1H), 3.08 (m, 1H), 1.17 (d, J=6.6 Hz, 3H). The couplingconstant between the methine protons was measured to 6.0 Hz. Comparisonwith the coupling constant of norephedrine, with known stereochemistry,indicated that the first eluting racemate has the(2R,3R)/(2S,3S)-configuration and the secondly eluting racemate has the(2R,3S)/(2S,3R)-configuration.

Example 71N-[(1R,2S)-1-[1-(4-Fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-(2-methoxyethoxy)acetamide

Prepared as described in Example 1 using(1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine(50 mg, 0.13 mmol) and 2-(2-methoxyethoxy)acetyl chloride (0.039 mL,0.38 mmol). Yield 52 mg (80%).

APCI-MS: m/z 508.4 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.01 (s, 1H), 7.67 (m, 2H), 7.59 (d, J=9.2Hz, 1H), 7.32-7.21 (m, 4H), 7.08 (d, J=2.3 Hz, 1H), 7.04-7.00 (m, 2H),6.84 (m, 1H), 5.34 (d, J=4.6 Hz, 1H), 4.41 (m, 1H), 3.92 (m, 2H), 3.77(s, 3H), 3.59-3.55 (m, 2H), 3.53-3.49 (m, 2H), 3.34 (s, 3H), 1.27 (d,J=6.9 Hz, 3H).

Example 722,2,2-Trifluoro-N-[(2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-yl]acetamide

Prepared as described in Example 1 using(2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-amine (60mg, 0.16 mmol) and trifluoroacetic anhydride (0.090 mL, 0.64 mmol).Yield 45 mg (60%).

APCI-MS: m/z 472.3 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 9.23 (dd, J=7.6 Hz, 1H), 8.05 (s, 1H), 7.67(m, 2H), 7.54 (d, J=9.2 Hz, 1H), 7.34-7.22 (m, 6H), 7.20-7.15 (m, 1H),7.12 (d, J=2.0 Hz, 1H), 7.02 (dd, J₁=9.2 Hz, J₂=2.1 Hz, 1H), 4.71 (m,1H), 4.23 (m, 1H), 3.01 (d, J=6.4 Hz, 2H), 1.39 (d, J=6.9 Hz, 3H).

(2S,3R)-3-[1-(4-Fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-amine(72a)

Prepared as described in Example 1 from(2S,3R)-3-hydroxy-4-phenylbutan-2-ammonium chloride (290 mg, 1.44 mmol)and 1-(4-fluorophenyl)-5-iodoindazole (583 mg, 1.73 mmol).

Yield 340 mg (63%).

¹H-NMR (400 MHz, CD₃OD): δ 8.07 (s, 1H), 7.68 (m, 2H), 7.56 (d, J=9.0Hz, 1H), 7.34-7.12 (m, 8H), 7.09 (dd, J₁=9.2 Hz, J₂=2.3 Hz, 1H), 4.52(m, 1H), 3.15 (m, 1H), 3.05 (m, 1H), 2.94 (m, 1H), 1.27 (d, J=6.5 Hz,3H).

(2S,3R)-3-Hydroxy-4-phenylbutan-2-ammonium chloride (72b)

Hydrochloric acid (5 to 6 M in isopropanol, 4 mL) was added to asolution of tert-butyl (2S,3R)-3-hydroxy-4-phenylbutan-2-ylcarbamate(640 mg, 2.41 mmol) in ethyl acetate (4 mL). The mixture was stirred at50° C. for 2.5 h and then concentrated. The solid was dissolved in warmethanol (4-5 mL). Diethyl ether (ca 15 mL) was added under stirring togive the subtitle compound as a light lilic precipitate (290 mg, 60%).

¹H-NMR (400 MHz, CD₃OD): δ 7.35-7.20 (m, 5H), 4.00 (m, 1H), 3.23 (m,1H), 2.79 (m, 2H), 1.32 (d, J=6.9 Hz, 3H).

tert-Butyl N-[(2S,3R)-3-hydroxy-4-phenyl-butan-2-yl]carbamate (72c)

Prepared as described in Example 6 from tert-butylN-[(2S)-3-oxo-4-phenyl-butan-2-yl]carbamate (650 mg, 2.47 mmol). Yield646 mg (99%; containing 15% of the (2S,3S)-diastereoisomer).

¹H-NMR (400 MHz, CD₂Cl₂): δ 7.34-7.28 (m, 2H), 7.25-7.20 (m, 3H), 4.81(broad s, 1H), 3.84 (m, 1H), 3.71 (m, 1H), 2.70 (m, 2H), 1.42 (s, 9H),1.16 (d, J=6.7 Hz, 3H).

tert-Butyl N-[(2S)-3-oxo-4-phenyl-butan-2-yl]carbamate (72d)

Prepared as described in Example 6 from (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (600 mg, 2.58 mmol)and benzylmagnesium chloride (2.0 M in THF, 3.87 mL, 7.75 mmol). Yield653 mg (96%).

¹H-NMR (400 MHz, CD₂Cl₂): δ 7.36-7.30 (m, 2H), 7.29-7.24 (m, 1H),7.21-7.17 (m, 2H), 5.18 (broad s, 1H), 4.35 (m, 1H), 3.81 (m, 2H), 1.42(s, 9H), 1.32 (d, J=7.1 Hz, 3H).

Example 73N-[(2S,3R)-3-[1-(4-Fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 1 using(2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-amine (60mg, 0.16 mmol) and pivaloyl chloride (0.078 mL, 0.64 mmol).

Yield 53 mg (72%).

APCI-MS: m/z 460.4 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.02 (s, 1H), 7.66 (m, 2H), 7.53 (d, J=9.0Hz, 1H), 7.34-7.21 (m, 6H), 7.19-7.13 (m, 1H), 7.07 (d, J=2.1 Hz, 1H),7.02 (dd, J₁=9.0 Hz, J₂=2.3 Hz, 1H), 4.74 (m, 1H), 4.14 (m, 1H), 2.99(d, J=6.4 Hz, 2H), 1.33 (d, J=6.9 Hz, 3H), 1.02 (s, 9H).

Example 74N-[(2S,3R)-3-[1-(4-Fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-yl]-2-hydroxy-acetamide

Prepared as described in Example 64 using(2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-amine (60mg, 0.16 mmol) and acetoxyacetyl chloride (0.069 mL, 0.64 mmol). Yield60 mg (87%).

APCI-MS: m/z 434.3 [MH⁺]

¹H-NMR (400 MJz, CD₃OD): δ 8.06 (s, 1H), 7.68 (m, 2H), 7.55 (d, J=9.0Hz, 1H), 7.35-7.22 (m, 6H), 7.19-7.14 (m, 2H), 7.06 (dd, J₁=9.0 Hz,J₂=2.3 Hz, 1H), 4.70 (m, 1H), 4.22 (m, 1H), 3.89 (s, 2H), 3.02 (m, 2H),1.35 (d, J=6.7 Hz, 3H).

Example 75 tert-Butyl[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]carbamoylformate

Prepared as described in Example 1 using(1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine(50 mg, 0.13 mmol) and tert-butyl 2-chloro-2-oxoacetate (0.064 mL, 0.40mmol) [prepared according to G. Bucher at al, Eur J Org Chem, 545-552(2001); b.p. 54-55° C., 21 mmHg]. Yield 44 mg (66%).

APCI-MS: m/z 520.4 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.01 (s, 1H), 7.66 (m, 2H), 7.59 (d, J=9.2Hz, 1H), 7.33-7.20 (m, 4H), 7.09 (m, 1H), 7.04-6.98 (m, 2H), 6.84 (broadd, J=8.3 Hz, 1H), 5.32 (d, J=5.3 Hz, 1H), 4.35 (m, 1H), 3.77 (s, 3H),1.50 (s, 9H), 1.33 (d, J=6.9 Hz, 3H).

Example 76N-[(1R,2S)-1-[1-(4-Fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]oxamide

N,N-Diisopropylamine (0.049 mL, 0.30 mmol) was added to a suspension of(1R,2S)-1-(1-(4-fluorophenyl)indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(53 mg, 0.14 mmol), 2-amino-2-oxoacetic acid (12 mg, 0.14 mmol) and HBTU(62 mg, 0.16 mmol.) in dichloromethane (2 mL). The mixture was stirredat r.t. overnight. The clear solution was concentrated and purified byHPLC to give the title compound (43 mg, 69%).

APCI-MS: m/z 463.3 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.00 (s, 1H), 7.66 (m, 2H), 7.59 (d, J=9.2Hz, 1H), 7.33-7.21 (m, 4H), 7.08 (d, J=2.3 Hz, 1H), 7.04-6.99 (m, 2H),6.83 (m, 1H), 5.34 (d, J=5.1 Hz, 1H), 4.35 (m, 1H), 3.77 (s, 3H), 1.31(d, J=6.9 Hz, 3H).

Example 77 Propan-2-yl[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]carbamoylformate

Prepared as described in Example 1 using(1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine(53 mg, 0.14 mmol) and isopropyl 2-chloro-2-oxoacetate (0.035 mL, 0.27mmol) [prepared according to G. Bucher at al, Eur J Org Chem, 545-552(2001); b.p. 54-55° C., 30 mmHg]. Yield 54 mg (79%).

APCI-MS: m/z 506.4 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.00 (s, 1H), 7.66 (m, 2H), 7.58 (d, J=9.2Hz, 1H), 7.32-7.21 (m, 4H), 7.08 (d, J=2.1 Hz, 1H), 7.04-6.99 (m, 2H),6.83 (m, 1H), 5.32 (d, J=5.3 Hz, 1H), 5.06 (m, 1H), 4.37 (m, 1H), 3.77(s, 3H), 1.34 (d, J=6.9 Hz, 3H), 1.29 (t, J=5.8 Hz, 6H).

Example 78 Ethyl[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]carbamoylformate

Prepared as described in Example 1 using(1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine(52 mg, 0.13 mmol) and ethyl 2-chloro-2-oxoacetate (0.030 mL, 0.27mmol). Yield 53 mg (81%).

APCI-MS: m/z 492.4 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.00 (s, 1H), 7.65 (m, 2H), 7.58 (d, J=9.2Hz, 1H), 7.32-7.20 (m, 4H), 7.07 (d, J=2.0 Hz, 1H), 7.04-6.98 (m, 2H),6.83 (m, 1H), 5.33 (d, J=5.1 Hz, 1H), 4.38 (m, 1H), 4.27 (m, 2H), 3.76(s, 3H), 1.34 (d, J=6.9 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H).

Example 79N-[(1R,2S)-1-[1-(4-Fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-N′-methyl-oxamide

Prepared as described in Example 76 using(1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine(51 mg, 0.13 mmol) and 2-(methylamino)-2-oxoacetic acid (13 mg, 0.13mmol). Yield 34 mg (55%).

APCI-MS: m/z 477.4 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.01 (s, 1H), 7.67 (m, 2H), 7.59 (d, J=9.2Hz, 1H), 7.32-7.21 (m, 4H), 7.07 (d, J=2.3 Hz, 1H), 7.03-6.99 (m, 2H),6.83 (m, 1H), 5.34 (d, J=5.0 Hz, 1H), 4.35 (m, 1H), 3.76 (s, 3H), 2.78(s, 3H), 1.31 (d, J=6.9 Hz, 3H).

Example 80N-[(1R,2S)-1-[1-(4-Fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-N′,N′-dimethyl-oxamide

Prepared as described in Example 76 using(1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine(51 mg, 0.13 mmol) and 2-(dimethylamino)-2-oxoacetic acid (13 mg, 0.13mmol). Yield 44 mg (69%).

APCI-MS: m/z 491.4 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.02 (s, 1H), 7.67 (m, 2H), 7.60 (d, J=9.2Hz, 1H), 7.33-7.21 (m, 4H), 7.10 (d, J=2.1 Hz, 1H), 7.06-7.01 (m, 2H),6.84 (m, 1H), 5.32 (d, J=5.1 Hz, 1H), 4.43 (m, 1H), 3.77 (s, 3H), 2.90(s, 3H), 2.78 (s, 3H), 1.32 (d, J=6.9 Hz, 3H).

Example 81N′-[(1R,2S)-1-[1-(4-Fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-N-propan-2-yl-oxamide

Prepared as described in Example 76 using(1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine(53 mg, 0.14 mmol) and 2-(isopropylamino)-2-oxoacetic acid (18 mg, 0.14mmol). Yield 42 mg (62%).

APCI-MS: m/z 505.4 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.01 (s, 1H), 7.67 (m, 2H), 7.60 (d, J=9.2Hz, 1H), 7.33-7.22 (m, 4H), 7.08 (d, J=2.1 Hz, 1H), 7.04-6.99 (m, 2H),6.84 (m, 1H), 5.34 (d, J=5.1 Hz, 1H), 4.35 (m, 1H), 3.97 (m, 1H), 3.77(s, 3H), 1.31 (d, J=6.9 Hz, 3H), 1.18 (d, J=6.6 Hz, 3H), 1.15 (d, J=6.7Hz, 3H).

Example 82N-[(1R,2S)-1-[1-(4-Fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-N′-tert-butyl-oxamide

Prepared as described in Example 76 using(1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine(51 mg, 0.13 mmol) and 2-(tert-butylamino)-2-oxoacetic acid (19 mg, 0.13mmol). Yield 53 mg (78%).

APCI-MS: m/z 519.4 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.01 (s, 1H), 7.67 (m, 2H), 7.60 (d, J=9.2Hz, 1H), 7.33-7.22 (m, 4H), 7.08 (d, J=2.1 Hz, 1H), 7.03-6.98 (m, 2H),6.84 (m, 1H), 5.33 (d, J=5.0 Hz, 1H), 4.33 (m, 1H), 3.77 (s, 3H), 1.35s, 9H), 1.31 (d, J=6.9 Hz, 3H).

Example 83N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)-4-(trifluoromethyl)benzamide

(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 28 mg, 0.07 mmol) and 4-(trifluoromethyl)benzoic acid (14 mg, 0.07mmol) were dissolved in DMF (0.265 ml). HBTU (30 mg, 0.08 mmol) andN,N-diisopropyl-ethylamine (0.026 ml, 0.16 mmol) were added and themixture was stirred over night at r.t. Then it was diluted withacetonitrile and purified by semi-preparative HPLC. Yield 24 mg (59%).

APCI-MS: m/z 564 [MH⁺]

1H NMR (300 MHz, d₆-dmso) δ 8.77 (d, J=8.2 Hz, 1H), 8.16 (d, J=0.8 Hz,1H), 7.98-7.78 (m, 4H), 7.77-7.65 (m, 3H), 7.45-7.34 (m, 2H), 7.30-7.19(m, 2H), 7.12 (d, J=2.3 Hz, 1H), 7.07-6.97 (m, 2H), 6.84-6.78 (m, 1H),5.41 (d, J=5.6 Hz, 1H), 4.47-4.34 (m, 1H), 3.70 (s, 3H), 1.33 (d, J=6.8Hz, 3H).

Example 84N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)oxazole-2-carboxamide

Prepared as described in Example 83 using(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 28 mg, 0.07 mmol) and oxazole-2-carboxylic acid (8 mg, 0.07 mmol).Yield 24 mg (69%).

APCI-MS: m/z 487 [MH⁺]

1H NMR (400 MHz, d₆-dmso) δ 8.83 (d, J=8.8 Hz, 1H), 8.28 (s, 1H), 8.18(s, 1H), 7.77-7.66 (m, 3H), 7.44-7.36 (m, 3H), 7.26-7.18 (m, 2H), 7.11(d, J=2.3 Hz, 1H), 7.04-6.96 (m, 2H), 6.80 (dd, J=8.1, 2.1 Hz, 1H), 5.39(d, J=6.5 Hz, 1H), 4.43-4.31 (m, 1H), 3.69 (s, 3H), 1.34 (d, J=6.7 Hz,3H).

Example 85N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)oxazole-4-carboxamide

Prepared as described in Example 83 using(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 28 mg, 0.07 mmol) and oxazole-4-carboxylic acid (8 mg, 0.07 mmol).Yield 26 mg (75%).

APCI-MS: m/z 487 [MH⁺]

1H NMR (300 MHz, d₆-DMSO) δ 8.58 (d, J=1.1 Hz, 1H), 8.50 (d, J=0.9 Hz,1H), 8.17 (d, J=0.8 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.78-7.66 (m, 3H),7.44-7.34 (m, 2H), 7.28-7.18 (m, 2H), 7.12 (d, J=2.1 Hz, 1H), 7.04-6.97(m, 2H), 6.83-6.77 (m, 1H), 5.45 (d, J=6.1 Hz, 1H), 4.47-4.33 (m, 1H),3.70 (s, 3H), 1.30 (d, J=6.8 Hz, 3H).

Example 86N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)furan-2-carboxamide

Prepared as described in Example 83 using(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 28 mg, 0.07 mmol) and furan-2-carboxylic acid (8 mg, 0.07 mmol).Yield 27 mg (78%).

APCI-MS: m/z 486 [MH⁺]

1H NMR (299.946 MHz, d₆-dmso) δ 8.33 (d, J=8.5 Hz, 1H), 8.16 (d, J=0.8Hz, 1H), 7.82-7.65 (m, 4H), 7.44-7.35 (m, 2H), 7.28-7.18 (m, 2H),7.12-7.05 (m, 2H), 7.03-6.95 (m, 2H), 6.80 (dd, J=8.2, 1.8 Hz, 1H), 6.58(dd, J=3.4, 1.7 Hz, 1H), 5.38 (d, J=5.8 Hz, 1H), 4.41-4.28 (m, 1H), 3.70(s, 3H), 1.30 (d, J=6.9 Hz, 3H).

Example 87N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)thiophene-2-carboxamide

Prepared as described in Example 83 using(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 28 mg, 0.07 mmol) and thiophene-2-carboxylic acid (9 mg, 0.07mmol). Yield 26 mg (72%).

APCI-MS: m/z 502 [MH⁺]

1H NMR (300 MHz, d₆-dmso) δ 8.54 (d, J=8.2 Hz, 1H), 8.16 (d, J=0.8 Hz,1H), 7.80-7.66 (m, 5H), 7.44-7.34 (m, 2H), 7.29-7.20 (m, 2H), 7.14-7.08(m, 2H), 7.04-6.96 (m, 2H), 6.81 (dd, J=8.2, 1.9 Hz, 1H), 5.40 (d, J=5.3Hz, 1H), 4.39-4.26 (m, 1H), 3.70 (s, 3H), 1.31 (d, J=6.9 Hz, 3H).

Example 88N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)pyrimidine-4-carboxamide

Prepared as described in Example 83 using(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 28 mg, 0.07 mmol) and pyrimidine-4-carboxylic acid (9 mg, 0.07mmol). Yield 12 mg (34%).

APCI-MS: m/z 498 [MH⁺]

1H NMR (300 MHz, d₆-dmso) δ 9.32 (d, J=1.3 Hz, 1H), 9.04 (d, J=5.0 Hz,1H), 8.88 (d, J=9.0 Hz, 1H), 8.17 (d, J=0.8 Hz, 1H), 7.94 (dd, J=5.0,1.3 Hz, 1H), 7.78-7.65 (m, 3H), 7.45-7.34 (m, 2H), 7.26-7.19 (m, 2H),7.14 (d, J=2.3 Hz, 1H), 7.04-6.98 (m, 2H), 6.83-6.76 (m, 1H), 5.51 (d,J=6.0 Hz, 1H), 4.53-4.39 (m, 1H), 3.68 (s, 3H), 1.34 (d, J=6.6 Hz, 3H).

Example 89N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)picolinamide

Prepared as described in Example 83 using(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 28 mg, 0.07 mmol) and picolinic acid (9 mg, 0.07 mmol). Yield 14 mg(39%).

APCI-MS: m/z 497 [MH⁺]

1H NMR (300 MHz, d₆-dmso) δ 8.69-8.59 (m, 2H), 8.16 (d, J=0.9 Hz, 1H),8.01-7.96 (m, 2H), 7.77-7.65 (m, 3H), 7.63-7.55 (m, 1H), 7.44-7.34 (m,2H), 7.28-7.20 (m, 2H), 7.15 (d, J=2.1 Hz, 1H), 7.05-6.99 (m, 2H),6.83-6.77 (m, 1H), 5.54 (d, J=5.4 Hz, 1H), 4.53-4.40 (m, 1H), 3.68 (s,3H), 1.31 (d, J=6.8 Hz, 3N).

Example 90N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(4-methoxyphenyl)propan-2-yl)pivalamide

Prepared as described in Example 83 using(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(4-methoxyphenyl)propan-2-amine(90a, 20 mg, 0.05 mmol) and Pivaloyl chloride (19 μl, 0.15 mmol). Yield13 mg (55%).

APCI-MS: m/z 476 [MH⁺]

¹H NMR (300 MHz, d₆-dmso) δ 8.17 (d, J=0.8 Hz, 1H), 7.79-7.64 (m, 3H),7.44-7.26 (m, 5H), 7.17 (dd, J=9.2, 2.4 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H),6.91-6.85 (m, 2H), 5.23 (d, J=6.5 Hz, 1H), 4.23-4.09 (m, 1H), 3.70 (s,3H), 1.22 (d, J=6.8 Hz, 3H), 0.94 (s, 9H).

(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(4-methoxyphenyl)propan-2-amine(90a)

Prepared as described in Example 6 using(1R,2S)-2-amino-1-(4-methoxy-phenyl)propan-1-ol hydrochloride (87 mg,0.40 mmol). Yield 43 mg (28%).

APCI-MS: m/z 392 [MH⁺]

(1R,2S)-2-amino-1-(4-methoxy-phenyl)propan-1-ol hydrochloride (90b)

Prepared as described in Example 6 using tert-butyl(1R,2S)-1-hydroxy-1-(4-methoxyphenyl)propan-2-ylcarbamate (130 mg, 0.46mmol). Yield 87 mg (86%).

APCI-MS: m/z 182 [MH⁺]

tert-butyl (1R,2S)-1-hydroxy-1-(4-methoxyphenyl)propan-2-ylcarbamate(90c)

Prepared as described in Example 6 using (S)-tert-butyl1-(4-methoxyphenyl)-1-oxopropan-2-ylcarbamate (0.45 g, 1.61 mmol). Yield389 mg (86%).

1H NMR (300 MHz, d₆-dmso) δ 7.24-7.18 (m, 2H), 6.88-6.82 (m, 2H), 6.51(d, J=8.8 Hz, 1H), 5.17 (d, J=4.6 Hz, 1H), 4.47-4.40 (m, 1H), 3.72 (s,3H), 3.58-3.46 (m, 1H), 1.30 (s, 9H), 0.93 (d, J=6.8 Hz, 3H).

(S)-tert-butyl 1-(4-methoxyphenyl)-1-oxopropan-2-ylcarbamate (90d)

Prepared as described in Example 6 usingtert-butyl{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate(0.462 g, 2.0 mmol) and 4-methoxymethylmagnesium-bromide (0.5M in THF,12 ml, 6.0 mmol). Yield 0.45 g (80%).

1H NMR (300 MHz, d₆-dmso) δ 7.99-7.92 (m, 2H), 7.23 (d, J=7.6 Hz, 1H),7.07-7.01 (m, 2H), 5.07-4.96 (m, 1H), 3.84 (s, 3H), 1.36 (s, 9H), 1.21(d, J=7.2 Hz, 3H).

Example 91N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylpentan-2-yl)-2-hydroxyacetamide

To a stirred solution of(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylpentan-2-amine(91a, 13 mg, 0.03 mmol) in dry THF (1 ml) were added, at r.t., triethylamine (28 μl, 0.2 mmol) and 2-chloro-2-oxoethyl acetate (10.8 μl, 0.1mmol). The reaction was stirred over night. The solvent was removedunder reduced pressure. To the crude solid was added Methanol (300 μl)and ammonium hydroxide (100 μl, 28%). The solution was stirred overnight.

The product was purified by preparative HPLC.

Yield. 14 mg (94%)

APCI-MS: m/z 448 [MH⁺]

1H NMR (399.99 MHz, dmso) δ 8.15 (s, 1H), 7.77-7.71 (m, 2H), 7.67 (d,J=26.2 Hz, 1H), 7.48 (d, J=26.2 Hz, 1H), 7.43-7.36 (m, 4H), 7.33 (t,J=13.1 Hz, 2H), 7.29-7.16 (m, 2H), 7.16-7.03 (m, 1H), 5.38 (d, J=51.8Hz, 1H), 4.19 (m, 1H), 3.76 (d, J=15.7 Hz, 1H), 3.68 (d, J=15.7 Hz, 1H),1.63 (m, 2H), 1.38 (m, 1H), 1.16 (m, 1H), 0.82 (t, J=7.3 Hz, 3H)

(1R,2S)-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylpentan-2-amine(91a)

In a vial under argon (1R,2S)-2-amino-1-phenylpentan-1-ol hydrochloride(91b, 46 mg, 0.21 mmol), 1-(4-fluorophenyl)-5-iodo-1H-indazole (87 mg,0.26 mmol), copper(I) iodide (8.12 mg, 0.04 mmol) and cesium carbonate(278 mg, 0.85 mmol) were mixed in butyronitrile (0.6 mL). The vial wassealed and heated to 125° C. for 16 h. The mixture was filtered throughcelite. The celite was washed with ethyl acetate. The collected organicphases were evaporated and the crude product was purified by preparativeHPLC. The pure fractions were collected, ethyl acetate and a saturatedsodium carbonate were added and the mixture was shaken. The organiclayer was separated and the water layer was washed twice with ethylacetate. The combined organic layers were dried over sodium sulphate andfinally evaporated to give the pure product.

Yield: 30 mg, 36%

APCI-MS: m/z 390 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (s, 1H), 7.76 (m, 2H), 7.66 (d, J=9.2Hz, 2H), 7.45-7.29 (m, 5H), 7.28-7.17 (m, 2H), 7.14 (d, J=2.1 Hz, 1H),5.14 (d, J=5.5 Hz, 1H), 3.03 (m, 1H), 1.61 (m, 2H), 1.44-1.14 (m, 4H),0.85 (t, J=6.9 Hz, 3H)

(1R,2S)-2-amino-1-phenylpentan-1-ol hydrochloride (91b)

(S)-tert-butyl 1-oxo-1-phenylpentan-2-ylcarbamate (91c, 190 mg, 0.69mmol) was dissolved in toluene under argon. Triisopropoxyaluminum (28.0mg, 0.14 mmol) was added followed by 2-propanol (0.573 ml, 7.54 mmol).The reaction was stirred at 50° C. over night. The solution wasevaporated. Ethyl acetate was added, the suspension was stirred andfinally filtered through celite. The eluent was evaporated and the crudeproduct was purified by Flash chromatography.

The pure tert-butyl (1R,2S)-1-hydroxy-1-phenylpentan-2-ylcarbamate wasdissolved in ethyl acetate (1.2 ml). Water (50 μl) and hydrochloric acidin ethyl acetate (1.0 ml, 1.5 M) were added. The solution was stirred at50° C. for 90 min. A precipitation was formed. The volume was reduced to⅔ by heavy stirring and a stream of argon gas. The stirring wascontinued for 1 h at r.t. The suspension was filtered and the solid wasdried at 50° C. under reduced pressure for 2 h.

Yield 59 mg, 39%

APCI-MS: m/z 180 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 3H), 7.43-7.23 (m, 5H), 6.03 (d,J=4.1 Hz, 1H), 4.99 (t, J=3.4 Hz, 1H), 3.25 (m, 1H), 1.31 (m, 3H), 1.03(m, 1H), 0.72 (t, J=7.1 Hz, 3H)

(S)-tert-butyl 1-oxo-1-phenylpentan-2-ylcarbamate (91c)

In a 50 mL round-bottomed flask was (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopentan-2-ylcarbamate (91d, 250 mg, 0.96mmol) dissolved in THF (9.6 ml). Phenylmagnesium bromide (2.88 ml, 2.88mmol) 1.0 M in THF was added. The reaction was stirred at r.t. for 5 h.The reaction was poured into a mixture of saturated ammonium chlorideand ethyl acetate. The mixture was shaken and the layers separated. Thewater layer was washed twice with ethyl acetate. The combined organiclayers were washed once with a small portion of water and dried oversodium sulphate. The solvent was evaporated and the crude product waspurified by flash chromatography.

Yield: 190 mg, 71%

APCI-MS: m/z 178 [MH⁺-BOC]

¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (m, 2H), 7.65 (t, J=21.4 Hz, 1H), 7.53(t, J=7.6 Hz, 2H), 7.28 (d, J=7.8 Hz, 1H), 4.95 (m, 1H), 1.61 (m, 1H),1.50 (m, 1H), 1.36 (m, 1H), 0.86 (t, J=7.3 Hz, 3H)

(S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopentan-2-ylcarbamate (91d)

Commercially available (2S)-2-[(tert-butoxycarbonyl)amino]pentanoic acid(1.0 g, 4.6 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.47 g,4.8 mmol) were dissolved in DMF (18 ml).O-benzotriazole-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate(1.92 g, 5.06 mmol) and N,N-diisopropylethylamine (2.47 ml, 14.5 mmol)were added. The reaction was stirred at r.t. over night. The reactionwas poured into a mixture of water and ethyl acetate. The mixture wasshaken, the layers separated and the water layer washed twice with ethylacetate. The collected organic phase was washed with a small portion ofwater and dried over sodium sulphate. The solvent was removed undereduced pressure and the crude product was purified by flashchromatography.

Yield. 1.02 g, 85%

APCI-MS: m/z 261 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 6.96 (d, J=8.3 Hz, 1H), 4.37 (m, 1H), 3.72(s, 3H), 3.09 (s, 3M), 1.36 (m, 13H), 0.85 (t, J=7.3 Hz, 3H)

Example 92N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylpentan-2-yl)pivalamide

To a stirred solution of(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylpentan-2-amine(91a, 13 mg, 0.03 mmol) dissolved in dry THF (150 μmol) were added, atr.t., triethylamine (27.8 μl, 0.20 mmol) and pivaloyl chloride (12.3 ul,0.1 mmo). The reaction was stirred over night. The solvent was removedunder reduced pressure, and the product purified by preparative HPLC.

Yield. 13 mg, 0.027 mmol, 91%

APCI-MS: m/z 474 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H), 7.73 (m, 2H), 7.66 (d, J=37.5Hz, 1H), 7.42-7.36 (m, 4H), 7.31 (t, J=7.5 Hz, 2H), 7.25-7.16 (m, 3H),7.11-7.07 (m, 1H), 5.25 (d, J=33.3 Hz, 1H), 4.16 (m, 1H), 1.70 (m, 2H),1.36 (m, 1H), 1.18 (m, 1H), 1.02 (s, 9H), 0.84 (t, J=7.3 Hz, 3H)

Example 93N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)pentan-2-yl)-2-hydroxyacetamide

was synthesised in the same way as example 131 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)pentan-2-amine(93a, 11 mg, 0.03 mmol).

The product was purified by preparative HPLC.

Yield. 12 mg, 92%

APCI-MS: m/z 478 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (s, 1H), 7.74 (m, 2H), 7.68 (d, J=9.2Hz, 1H), 7.48 (d, J=9.6 Hz, 1H), 7.39 (m, 2H), 7.28-7.18 (m, 2H),7.12-7.07 (m, 1H), 6.99-6.93 (m, 2H), 5.35 (d, J=5.5 Hz, 1H), 4.20 (m,1H), 3.77 (d, J=15.7 Hz, 1H), 3.72 (s, 3H), 3.70 (d, J=16.6 Hz, 1H),1.64 (m, 2H), 1.40 (m, 1H), 1.13 (m, 1H), 0.83 (t, J=7.3 Hz, 3H)

(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)pentan-2-amine(93a)

was synthesised in the same way as (91a) from(1R,2S)-2-amino-1-(3-methoxyphenyl)pentan-1-ol hydrochloride (93b, 50mg, 0.20 mmol).

The product was purified by preparative HPLC.

Yield. 26 mg, 31%

APCI-MS: m/z 420 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (d, J=0.7 Hz, 1H), 7.74 (m, 2H), 7.66(d, J=9.2 Hz, 2H), 7.39 (t, J=8.8 Hz, 2H), 7.25 (m, 2H), 7.15 (d, J=2.1Hz, 1H), 7.00 (m, 2H), 6.82 (m, 1H), 5.10 (d, J=5.3 Hz, 1H), 3.72 (s,3H), 3.02 (m, 1H), 1.62-1.13 (m, 6H), 0.86 (t, J=7.0 Hz, 3H)

(1R,2S)-2-amino-1-(3-methoxyphenyl)pentan-1-ol hydrochloride (93b)

was synthesised in the same way as 91b from (S)-tert-butyl1-(3-methoxyphenyl)-1-oxopentan-2-ylcarbamate (213 mg, 0.693 mmol).

Yield. 102 mg, 59%

APCI-MS: m/z 210 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (s, 3H), 7.29 (t, J=7.9 Hz, 3H), 6.94(m, 6H), 6.85 (m, 2H), 6.03 (d, J=4.1 Hz, 1H), 4.93 (s, 1H), 3.76 (s,3H), 3.28 (m, 1H), 1.44-1.20 (m, 3H), 1.19-1.05 (m, 1H), 0.74 (t, J=7.0Hz, 3H)

(S)-tert-butyl 1-(3-methoxyphenyl)-1-oxopentan-2-ylcarbamate (93c)

was synthesised in the same way as (91c) from (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopentan-2-ylcarbamate (91d, 250 mg, 0.96mmol).

Yield. 213 mg, 72%

APCI-MS: m/z 208 [MH⁺-BOC]

¹H NMR (400 MHz, DMSO-d₆) δ 7.55 (d, J=7.6 Hz, 1H), 7.44 (m, 2H), 7.27(d, J=8.0 Hz, 1H), 7.21 (m, 1H), 4.93 (m, 1H), 3.81 (s, 3H), 1.61 (m,1H), 1.49 (m, 1H), 1.35 (m, 1H), 0.86 (t, J=7.3 Hz, 3H)

Example 94N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)pentan-2-yl)pivalamide

was synthesised in the same way as example 92 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)pentan-2-amine(93a, 11 mg, 0.03 mmol)

The product was purified by preparative HPLC.

Yield. 13 mg, 98%

APCI-MS: m/z 504 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (s, 1H), 7.74 (m, 2H), 7.68 (d, J=9.0Hz, 1H), 7.39 (t, J=8.8 Hz, 2H), 7.25-7.16 (m, 3H), 7.10 (m, 1H),6.99-6.92 (m, 2H), 5.21 (d, J=6.9 Hz, 1H), 4.14 (m, 1H), 3.72 (s, 3H),1.69 (m, 2H), 1.34 (m, 1H), 1.19 (m, 1H), 0.94 (s, 9H), 0.85 (t, J=7.3Hz, 3H)

Example 95N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylbutan-2-yl)-2-hydroxyacetamide

was synthesised in the same way as example 131 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylbutan-2-amine(95a, 10 mg, 0.03 mmol). The product was purified by preparative HPLC.

Yield. 12 mg, 100%

APCI-MS: m/z 434 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (s, 1H), 7.73 (m, 2H), 7.68 (d, J=9.0Hz, 1H), 7.48 (d, J=31.2 Hz, 1H), 7.43-7.36 (m, 4H), 7.33 (t, J=7.5 Hz,2H), 7.27-7.17 (m, 2H), 7.11-7.07 (m, 1H), 5.38 (d, J=5.7 Hz, 1H), 4.13(m, 1H), 3.77 (d, J=15.7 Hz, 1H), 3.69 (d, J=15.7 Hz, 1H), 1.73 (m, 1H),1.58 (m, 1H), 0.83 (t, J=7.3 Hz, 3H).

(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylbutan-2-amine(95a)

was synthesised in the same way as (91a) from(1R,2S)-2-amino-1-phenylbutan-1-ol hydrochloride (95b, 53 mg, 0.26mmol).

The product was purified by preparative HPLC.

Yield. 23 mg, 24%

APCI-MS: m/z 376 [MH⁺]

¹H NMR (400 MHz, DMSO-d) δ 8.14 (s, 1H), 7.75 (m, 2H), 7.66 (d, J=9.2Hz, 1H), 7.46-7.30 (m, 6H), 7.25 (m, 1H), 7.19 (m, 1>, 7.14 (d, J=2.1Hz, 1H), 5.14 (d, J=5.5 Hz, 1H), 2.95 (m, 1H), 1.67 (m, 1H), 1.29 (m,3H), 0.95 (t, J=7.3 Hz, 3H)

(1R,2S)-2-amino-1-phenylbutan-1-ol (95b)

was synthesised in the same way as 90b from (S)-tert-butyl1-oxo-1-phenylbutan-2-ylcarbamate (95c, 209 mg, 0.795 mmol).

Yield. 60 mg, 38%

APCI-MS: m/z 166 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (s, 3H), 7.33 (m, 5H), 6.03 (d, J=4.2Hz, 1H), 4.97 (t, J=3.6 Hz, 1H), 3.20 (quintet, J=4.0 Hz, 1H), 1.51-1.27(m, 2H), 0.79 (t, J=7.5 Hz, 3H).

(S)-tert-butyl 1-oxo-1-phenylbutan-2-ylcarbamate (95c)

was synthesised in the same way as (91c) from (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxobutan-2-ylcarbamate (95d, 250 mg, 1.02mmol).

Yield. 209 mg, 78%

APCI-MS: m/z 164 [MH⁺-BOC]

¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (d, J=7.3 Hz, 2H), 7.64 (t, J=7.3 Hz,1H), 7.53 (t, J=7.7 Hz, 2H), 7.26 (d, J=7.8 Hz, 1H), 4.89 (m, 1H), 1.72(m, 1H), 1.53 (m, 1H), 1.37 (s, 8H), 0.90 (t, J=7.3 Hz, 3H).

(S)-tert-Butyl 1-(methoxy(methyl)amino)-1-oxobutan-2-ylcarbamate (95d)

was synthesised in the same way as (91d) from commercially available(2S)-2-[(tert-butoxycarbonyl)amino]butanoic acid (0.935 g, 4.60 mmol).

Yield. 0.987 g, 87%

APCI-MS: m/z 191[MH⁺-56]

¹H NMR (400 MHz, DMSO-d₆) δ6.96 (d, J=8.0 Hz, 1H), 4.29 (m, 1H), 3.72(s, 3H), 3.10 (s, 3H), 1.53 (m, 2H), 1.37 (s, 9H), 0.86 (t, J=7.3 Hz,3H)

Example 96N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylbutan-2-yl)pivalamide

Was synthesised in the same way as example 132 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylbutan-2-amine(96a, 10 mg, 0.03 mmol). The product was purified by preparative HPLC.

Yield. 11 mg, 90%

APCI-MS: m/z 460 [MH⁺]

¹H NMR (399.99 MHz, dmso) δ 8.16 (s, 1H), 7.76-7.70 (m, 2H), 7.67 (d,J=9.2 Hz, 1H), 7.43-7.36 (m, 4H), 7.31 (t, J=7.4 Hz, 2H), 7.25-7.16 (m,3H), 7.09 (m, 1H), 5.24 (d, J=7.3 Hz, 1H), 4.07 (m, 1H), 1.82 (m, 1H),1.67 (m, 1H), 0.93 (s, 9H), 0.83 (t, J=7.4 Hz, 3H)

Example 97N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)butan-2-yl)-2-hydroxyacetamide

was synthesised in the same way as example 131 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)butan-2-amine(97a, 13 mg, 0.03 mmol)

The product was purified by preparative HPLC.

Yield. 11 mg, 74%

APCI-MS: m/z 464 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (s, 1H), 7.82 (m, 2H), 7.68 (d, J=9.2Hz, 1H), 7.48 (d, J=9.4 Hz, 1H), 7.39 (m, 2H), 7.29-7.17 (m, 2H), 7.10(m, 1H), 6.98 (m, 2H), 6.82 (m, 1H), 5.36 (d, J=5.7 Hz, 1H), 4.12 (m,1H), 3.78 (d, J=15.7 Hz, 1H), 3.72 (s, 3H), 3.71 (d, J=14.0 Hz, 1H),1.72 (m, 1H), 1.59 (m, 1H), 0.84 (t, J=7.3 Hz, 3H)

(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)butan-2-amine(97a)

was synthesised in the same way as (91a) from(1R,2S)-2-amino-1-(3-methoxyphenyl)butan-1-ol hydrochloride (97b, 50 mg,0.22 mmol).

The product was purified by preparative HPLC. Yield. 30 mg, 34%

APCI-MS: m/z 406 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (s, 1H), 7.73 (m, 2H), 7.66 (d, J=9.0Hz, 2H), 7.39 (t, J=8.8 Hz, 2H), 7.29-7.17 (m, 4H), 7.15 (d, J=2.1 Hz,2H), 6.97 (m, 2H), 6.82 (m, 1H), 5.10 (d, J=5.7 Hz, 1H), 3.72 (s, 4H),2.93 (m, 1H), 1.63 (m, 1H), 1.24 (m, 1H), 0.95 (t, J=7.4 Hz, 3H).

(1R,2S)-2-amino-1-(3-methoxyphenyl)butan-1-ol (97b)

was synthesised in the same way as 90b from (S)-tert-butyl1-oxo-1-phenylbutan-2-ylcarbamate (97c, 225 mg, 0.768 mmol).

Yield. 115 mg, 65%

APCI-MS: m/z 196 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (s, 3H), 7.28 (t, J=7.8 Hz, 1H), 6.95(m, 2H), 6.85 (m, 1H), 6.03 (d, J=4.1 Hz, 1H), 4.93 (t, J=3.5 Hz, 1H),3.76 (s, 3H), 3.21 (m, 1H), 1.38 (m, 2H), 0.81 (t, J=7.5 Hz, 3H).

(S)-tert-butyl 1-(3-methoxyphenyl)-1-oxobutan-2-ylcarbamate (97c)

was synthesised in the same way as 91c from (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxobutan-2-ylcarbamate (95d, 250 mg, 1.02mmol).

Yield. 225 mg, 75%

APCI-MS: m/z 194 [MH⁺-BOC]

¹H NMR (400 MHz, DMSO-d₆) δ 7.56 (d, J=7.8 Hz, 1H), 7.45 (m, 2H), 7.23(m, 2H), 4.88 (m, 1H), 3.81 (s, 3H), 1.71 (m, 1H), 1.52 (m, 1H), 1.36(s, 9H), 0.89 (t, J=7.3 Hz, 3H).

Example 98N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)butan-2-yl)pivalamide

was synthesised in the same way as example 92 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)butan-2-amine(97a, 13 mg, 0.03 mmol). The product was purified by preparative HPLC.Yield. 12 mg, 76%.

APCI-MS: m/z 490 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (s, 1H), 7.74 (m, 2H), 7.68 (d, J=9.2Hz, 1H), 7.39 (m, 2H), 7.20 (m, 3H), 7.09 (m, 1H), 6.97 (m, 2H), 6.79(m, 1H), 5.21 (d, J=7.1 Hz, 1H), 4.05 (m, 1H), 3.72 (s, 3H), 1.79 (m,1H), 1.66 (m, 1H), 0.95 (s, 9H), 0.83 (t, J=7.3 Hz, 3H)

Example 99N-[(1RS,2SR)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-yl]-2,2,2-trifluoro-acetamide

(1RS,2SR)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine(99a-rac-2, 10 mg, 0.02 mmol) and TEA (100 μl) in MeCN (1 ml) were mixedand trifluoroacetic anhydride (10 μl, 0.07 mol) was added. The mixturewas stirred at r.t. over night. The title compound (10 mg, 82%) wasobtained by preparative HPLC (water/MeCN/1% TFA).

¹H NMR (400 MHz, CD₃OD) δ 9.29 (d, J=8.3 Hz, 1H), 8.02 (s, 1H), 7.78 (s,1H), 7.67 (dd, J=8.9, 4.7 Hz, 2H), 7.47 (dd, J=8.7, 5.3 Hz, 2H), 7.31(t, J=8.7 Hz, 2H), 7.16 (s, 1H), 7.09 (t, J=8.8 Hz, 2H), 5.44 (d, J=6.0Hz, 1H), 4.47-4.39 (m, 1H), 1.44 (d, J=6.7 Hz, 3H).

APCI-MS: 510 m/z [MH⁺].

1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine(99a)

1-{[6-Chloro-1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(4-fluorophenyl)acetone(500 mg, 1.21 mmol), ammonium acetate (934 mg, 12.11) andcyanoborohydride on polymer support (1.82 g, 3.63 mmol) were mixed inmethanol (3 ml) and heated in micro at 140° C. for 10 min. The mixturewas concentrated and treated with NaHCO₃ and DCM. The organic phase wasconcentrated and the crude product was purified by flash chromatography(EtOAc/heptane followed by EtOAc/methanol). The diasteromers wereseparated on preparative HPLC (Kromasil column, water buffered with 2 gNH₄OAc/l, pH set to 5.5 with HOAc, and MeCN, 25%-75%) to give thesyn-isomer(1RS,2RS)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine(98a-rac-1) as first eluted isomer (assignment by 1H-NMR).

¹H NMR (400 MHz, CD₃OD) δ 8.05 (d, J=0.9 Hz, 1H), 7.75 (s, 1H), 7.65(tt, J=4.6, 2.3 Hz, 2H), 7.53 (dd, J=12.0, 1.9 Hz, 2H), 7.34-7.26 (m,3H), 7.13 (t, J=8.8 Hz, 2H), 5.28 (d, J=8.3 Hz, 1H), 3.69 (dd, J=8.2,6.8 Hz, 1H), 1.17 (d, J=6.7 Hz, 3H).

APCI-MS: 414 m/z [MH⁺].

The anti-isomer(1RS,2SR)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine(99a-rac-2) was eluted secondly.

¹H NMR (400 MHz, CD₃OD) δ 8.02 (s, 1H), 7.79 (s, 1H), 7.69-7.64 (m, 2H),7.48-7.43 (m, 2H), 7.31 (dd, J=20.8, 3.4 Hz, 2H), 7.18-7.10 (m, 3H),5.41 (d, J=4.6 Hz, 1H), 3.46 (dt, J=11.1, 6.6 Hz, 1H), 1.27 (d, J=6.5Hz, 3H).

APCI-MS: 414 m/z [MH⁺].

1-{[6-chloro-1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(4-fluorophenyl)acetone(99b)

4-Fluorophenylacetone (388 μl, 2.9 mmol) in DCM (12 ml) was cooled to 0°C. and bromine (672 mg, 2.9 mmol) was slowly added. The mixture wasstirred for 30 min and then concentrated in vacuo. The crudeintermediate was added to a mixture of6-chloro-1-(4-fluorophenyl)-1H-indazol-5-ol, (99c) (762 mg, 2.9 mmol)and potassium carbonate (804 mg, 5.8 mmol) in THF (12 ml). The mixturewas stirred for 4 h, filtrated and concentrated. The crude product waspurified by flash chromatography (EtOAc/heptane, product eluted at 40%EtOAc) to give the title compound (1.06 g, 88%).

APCI-MS: 413 m/z [MH⁺].

6-Chloro-1-(4-fluorophenyl)-1H-indazol-5-ol (99c)

1-(4-Fluorophenyl)-6-chloro-5-methoxy-1H-indazole (99d) (0.91 mmol, 253mg) was dissolved in dichloromethane (4 mL) and BBr₃ (4 mL, 1 M/CH₂Cl₂)was added. The reaction mixture was stirred in room temperatureovernight before it was quenched with water (20 mL). The product wasextracted with dichloromethane (2×20 mL) and washed with sat NaHCO₃. Theorganic phase was dried over Na₂SO₄, concentrated and purified by flashchromatography on silica gel (heptane-ethyl acetate). Yield: 219 mg(91%).

¹H NMR (500 MHz, CDCl₃) δ 8.09 (d, J=0.7 Hz, 1H), 7.70 (s, 1H),7.67-7.60 (m, 2H), 7.37 (s, 1H), 7.28-7.23 (m, 2H), 5.43 (s, 1H).

APCI-MS m/z (method A): 360.0 [MH⁺].

1-(4-Fluorophenyl)-6-chloro-5-methoxy-1H-indazole (99d)

4-Chloro-2-fluoro-5-methoxy benzaldehyde (204 mg, 1.1 mmol) and4-fluorophenylhydrazine (176 mg, 1.1 mmol) were dissolved inN-methylpyrrolidine (5 mL). After addition of cesium carbonate (1.15 g,3.3 mmol) the mixture was heated in a microwave reactor (CEM Discovery,150 Watt) to 150° C. for 20 min. After dilution with DCM the mixture waswashed with sat. NaHCO₃, brine and the organic phase was evaporated.After purification of the crude by flash chromatography on silica gel253 mg (84%) of the subtitle compound were obtained.

APCI-MS: 277.0 m/z [MH⁺].

Example 100N-[(1RS,2SR)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-yl]acetamide

The title compound was made from(1RS,2RS)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine(99a-rac-1) and purified on preparative HPLC (water/MeCN/1% TFA).

¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, J=0.7 Hz, 1H), 7.75 (s, 1H), 7.65(tt, J=4.6, 2.3 Hz, 2H), 7.45 (dd, J=8.7, 5.5 Hz, 2H), 7.30 (t, J=8.9Hz, 2H), 7.24 (s, 1H), 7.10 (t, J=8.8 Hz, 2H), 5.44 (d, J=5.3 Hz, 1H),4.48 (dd, J=6.7, 5.7 Hz, 1H), 1.96 (s, 3H), 1.18 (d, J=6.9 Hz, 3H).

APCI-MS: 456 m/z [MH⁺].

Example 101N-[(1S*,2R*)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-yl]acetamide

The title compound was obtained by acylation of(1RS,2SR)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine(99a-rac-2) followed by separation using chiral HPLC (Chiralpak IA;isohexane/ethanol 4:1) The title compound was obtained as the firsteluted enantiomer.

APCI-MS: 456 m/z [MH⁺]

¹H NMR (400 MHz, CD₃OD) δ 8.01 (d, J=0.9 Hz, 1H), 7.78 (s, 1H),7.69-7.64 (m, 2H), 7.45 (dd, J=12.0, 1.9 Hz, 2H), 7.31 (t, J=8.7 Hz,2H), 7.12-7.06 (m, 3H), 5.49 (d, J=4.4 Hz, 1H), 4.31 (dt, J=11.4, 6.9Hz, 1H), 1.89 (s, 3H), 1.30 (d, J=6.9 Hz, 3H)

Example 102N-[(1R*,2S*)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-yl]acetamide

Obtained from the separation described in Example 101 as the secondlyeluted enantiomer.

¹H NMR (400 MHz, CD₃OD) δ 8.01 (d, J=0.9 Hz, 1H), 7.78 (s, 1H), 7.66(dd, J=17.2, 3.5 Hz, 2H), 7.45 (dd, J=12.0, 1.9 Hz, 2H), 7.31 (ddd,J=12.3, 8.5, 3.7 Hz, 2H), 7.12-7.06 (m, 3H), 5.49 (d, J=4.6 Hz, 1H),4.31 (dt, J=11.3, 6.9 Hz, 1H), 1.89 (s, 3H), 1.30 (d, J=6.9 Hz, 3H).

APCI-MS: 456 m/z [MH⁺].

Example 1032,2,2-trifluoro-N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-ylthio)-1-phenylpropan-2-yl)acetamide

To(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-ylthio)-1-phenylpropan-2-amine(0.024 g, 0.06 mmol) in MeOH (2.5 mL), 1,1,3,3-tetramethylguanidine(0.056 mL, 0.45 mmol) and ethyl trifluoroacetate (0.114 mL, 0.95 mmol)was added and the mixture was stirred at rt O/N and than submitted topurification on HPLC. The relevant fractions were collected freeze driedto give 16 mg of product (53% yield) which was analysed by LC/MS andNMR.

APCI-MS: m/z 474 [MH⁺].

¹H NMR (400 MHz, d₆-DMSO) δ 9.34 (s, 1H), 8.30 (s, 1H), 7.79-7.73 (m,3H), 7.68 (d, J=8.8 Hz, 1H), 7.42 (t, J=8.8 Hz, 2H), 7.32 (d, J=9.3 Hz,1H), 7.21 (dd, J=11.5, 6.9 Hz, 4H), 4.40 (s, 1H), 4.38-4.28 (m, 1H),1.42 (d, J=6.5 Hz, 3H).

(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-ylthio)-1-phenylpropan-2-amine(103a)

ToN-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-ylthio)-1-phenylpropan-2-yl)-2-(trimethylsilyl)ethanesulfonamide(103a, 0.042 g, 0.08 mmol) in DMF (2 mL) cesium fluoride (8.60 μL, 0.23mmol) was added and the mixture was stirred at 95° C. Stirring wascontinued at that temperature O/N. Cooled at rt the solvent was removedand the mixture was partitioned between EtOAc/water the organic phasewas than purified with HPLC The relevant fractions were collected freezedried to give 24 mg of product (84% yield) which was analysed by LC/MS.

APCI-MS: m/z 378 [MH⁺]

N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-ylthio)-1-phenylpropan-2-yl)-2-(trimethylsilyl)ethanesulfonamide(103b)

To(2R,3R)-2-methyl-3-phenyl-1-(2-(trimethylsilyl)ethylsulfonyl)aziridine(103c, 0.068 g, 0.23 mmol) in THF (2 mL)1-(4-fluorophenyl)-1H-indazole-5-thiol (0.056 g, 0.23 mmol) and sodiumhydride dispertion, 55-60% in oil (10.97 mg, 0.46 mmol) was added andthe mixture was stirred at r.t. LC/MS after 2 h showed product, stirringwas continued at 40 C for 4 h than this mixture was stirred O/N at r.t.The mixture was separated between water and EtOAc and the organic phasewas purified with HPLC. The relevant fractions were collected freezedried to give 12 mg of product (10% yield) which was analysed by LC/MS.

APCI-MS: m/z 543.1 [MH⁺]

(2R,3R)-2-methyl-3-phenyl-1-(2-(trimethylsilyl)ethylsulfonyl)aziridine(103c)

To (2R,3R)-2-methyl-3-phenylaziridine (103d, 0.05 g, 0.38 mmol) in THF(3 mL) at −10° C. N,N-diisopropylamine (0.124 mL, 0.75 mmol) was addedand stirred for 5 min before(2R,3R)-2-methyl-3-phenyl-1-(2-(trimethylsilyl)ethylsulfonyl)aziridine(8.00 mg, 7.16%) in THF (1 ml) was added in small portions. Theacetone/ice bath was than removed and the mixture was stirred for 1 hrat r.t. before the solvent was removed the mixture was dilute in MeCN anpurified on HPLC. The relevant fractions were collected freeze dried togive 8 mg (7%) of product which was analysed by LC/MS.

APCI-MS: m/z 339.1 [MH⁺+MeCN]

S-1-(4-fluorophenyl)-1H-indazol-5-yl benzothioate (103d)

To a solution of 1-(4-fluorophenyl)-5-iodo-1H-indazole (103e, 0.224 g,0.66 mmol), thiobenzoic acid (0.093 ml, 0.79 mmol),3,4,7,8-tetramethyl-1,10-phenantroline (0.031 g, 0.13 mmol) andN,N-diisopropylamine (0.220 ml, 1.32 mmol) in toluene (2.5 ml) was addedcopper(I) iodine (2.245 μl, 0.07 mmol). The resulting mixture wasstirred at 110 C O/N. The reaction mixture was cooled to r.t. dilutedwith EtOAc and washed with water. The organic phase was the dried thesolvent evaporated and then purified on HPLC. The relevant fractionswere collected freeze dried to give 45 mg of product (20% yield) whichwas analysed by LC/MS.

APCI-MS: m/z 349 [MH⁺]

1-(4-fluorophenyl)-1H-indazole-5-thiol (103e)

To S-1-(4-fluorophenyl)-1H-indazol-5-yl benzothioate (0.046 g, 0.13mmol) in methanol (3 mL), potassium carbonate (0.011 mL, 0.20 mmol) wasadded and the mixture was stirred at r.t. for 2 h. water was than added,1N HCl (2 ml) and extracted with EtOAc (2*20 ml), dried, evaporated andthen purified on HPLC. The relevant fractions were collected freezedried and analysed by LC/MS.

APCI-MS: m/z 245 [MH⁺].

Example 1041-(Cyclopentyl)-3-{(1S,2R)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl)oxy]-1-methyl-2-phenyl-ethyl}urea

(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine(100 mg, 0.28 mmol), as described in Example 1, is dissolved in 1.77 mLdichloromethane and cyclopentylisocyanate (0.031 mL, 0.28 mmol) isdropwise added. After stirring for 45 min at r.t. the solvent is removedand the residue purified by chromatography (silicagel, eluents:hexane/ethyl acetate). 94.8 mg (72.5%) of the title compound areobtained.

MS (CI): 473 (M+)

¹H-NMR (300 MHz, CDCl₃):

=1.17 (3H), 1.22-1.45 (2H), 1.49-1.72 (4H), 1.82-2.03 (2H), 3.90-4.02(1H), 4.19-4.80 (3H), 5.42 (1H), 6.98 (1H), 7.10-7.49 (8H), 7.50-7.70(3H), 7.97 (1H).

Example 1051-{(1S,2R)-2-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-1-methyl-2-phenylethyl}-3-(2-furylmethyl)urea

(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine(100 mg, 0.28 mmol), as described in Example 1, is dissolved in 1.77 mLdichloromethane and furylmethylisocyanate (34.1 mg, 0.28 mmol) isdropwise added. After stirring for 45 min at r.t. the solvent is removedand the residue purified by chromatography (silicagel, eluents:hexane/ethylacetate). 116.2 mg (86.7%) of the title compound areobtained.

MS (EI+): 484 (M)

¹H-NMR (400 MHz, CDCl₃):

=1.13 (3H), 4.22-4.45 (3H), 4.70-4.95 (broad, 2H), 5.43 (1H), 6.19 (1H),6.29 (1H), 6.93 (1H), 7.12 (1H), 7.16-7.44 (8H), 7.52 (1H), 7.57-7.68(2H), 7.95 (1H).

Example 106 EthylN-{[(1S,2R)-2-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-methyl-2-phenylethyl]carbamoyl}glycinate

(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine(80 mg, 0.22 mmol), as described in Example 1, is dissolved in 1.42 mLdichloromethane and ethylisocyanatoacetate (28.6 mg, 0.22 mmol) isdropwise added. After stirring for 45 min at r.t. the solvent is removedand the residue purified by chromatography (silicagel, eluents:hexane/ethylacetate). 85.4 mg (78.6%) of the title compound areobtained.

MS (CI+): 491 (M+)

¹H-NMR (400 MHz, CDCl₃):

=1.19 (3H), 1.29 (3H), 3.89-4.32 (5H), 4.82-5.12 (broad, 2H), 5.42 (1H),6.96 (1H), 7.12-7.45 (8H), 7.55 (1H), 7.58-7.65 (2H), 7.96 (1H).

Example 1071-((R)-1,2-Dimethylpropyl)-3-{(1S,2R)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-1-methyl-2-phenylethyl}urea

(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine(50 mg, 0.14 mmol), as described in Example 1, is dissolved in 0.89 mLdichloromethane and (R)-(−)-3-methyl-2-butylisocyanate (15.7 mg, 0.14mmol) is dropwise added. After stirring for 90 min at r.t. the solventis removed and the residue purified by chromatography (silicagel,eluents: hexane/ethylacetate). 50.6 mg (77.1%) of the title compound areobtained.

MS (CI): 475 (M+)

¹H-NMR (300 MHz, CDCl₃):

=0.85-0.95 (6H), 1.10 (3H), 1.29 (3H), 1.69 (1H), 3.67 (1H), 4.00-4.70(extremely broad, 2H), 4.30 (1H), 5.50 (1H), 7.03 (1H), 7.17-7.49 (8H),7.58 (1H), 7.61-7.70 (2H), 8.00 (1H).

Example 1081-{(1S,2R)-2-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-1-methyl-2-phenylethyl}-3-(2-furylmethyl)thiourea

(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine(50 mg, 0.14 mmol), as described in Example 1, is dissolved in 0.89 mLdichloromethane and furylmethylisothiocyanate (19.3 mg, 0.14 mmol) isdropwise added. After stirring for 90 min at r.t. water (5 mL) is addedand the reaction mixture extracted once with ethyl acetate (50 mL). Theorganic phase is washed with water (10 mL) and dried over Na₂SO₄. Afterfiltration the solvent is removed and the residue purified bychromatography (silicagel, eluents: hexane/ethylacetate). 53.8 mg(77.7%) of the title compound are obtained.

MS (CI+): 501 (M+)

¹H-NMR (300 MHz, CDCl₃):

=1.28 (3H), 4.52-4.92 (3H), 5.60 (1H), 6.08-6.68 (4H), 6.97 (1H), 7.19(1H), 7.18-7.50 (8H), 7.55 (1H), 7.58-7.70 (2H), 8.00 (1H).

Example 109

N-{(1S)-1-[(R)-(3-Fluorophenyl)-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}methyl]-3-methyl-butyl}-2-methoxyacetamide

N-(tert.-Butoxycarbonyl)-L-leucinal

Lithiumaluminiumhydride (863.5 mg, 22.8 mmol) is added in portions at10° C. to N-(tert.-butoxycarbonyl)-L-leucine-N′-methoxy-N′-methylamide(5 g, 18.2 mmol), dissolved in diethylether (500 mL). After stirring ofthe reaction mixture for 1 h at r.t., a solution of 4.34 g KHSO₄ in 91mL water is added carefully at 10° C. Afterwards the reaction mixture isvigorously stirred for 30 min and the organic phase separated. Aftertwice extraction of the aqueous phase with diethylether the combinedorganic phases are washed with water and brine and dried over Na₂SO₄.The solvent is removed and the residue (4.3 g, >100%) is used withoutfurther purification in the next step.

MS (CI+): 216 (M+)

¹H-NMR (300 MHz, CDCl₃):

=0.85-1.02 (6H), 1.32-1.86 (12H), 4.24 (1H), 4.91 (1H), 9.59 (1H).

{(S)-1-[(3-Fluorophenyl)-hydroxymethyl]-3-methylbutyl}-carbamic acidtert.-butylester

An 1M 3-Fluorophenylgrignard solution (58.5 mL, 58.5 mmol) is addeddropwise under nitrogen and water bath cooling toN-(tert.-butoxycarbonyl)-L-leucinal (4.2 g, 19.5 mmol), dissolved in50.5 mL diethylether (the temperature rises to 30° C.). The reactionmixture is stirred for 2 h at r.t. and then poured on NH₄Cl/ice. Afterextraction with diethylether (three times) the combined organic phasesare washed with water and brine. The solvent is dried over Na₂SO₄ andevaporated. The residue is finally purified by chromatography(silicagel, eluents: ethylacetate/hexane). 4.7 g (77.4%) of the titlecompound as a mixture of two stereoisomers are obtained.

MS (CI+): 312 (M+)

¹H-NMR (300 MHz, CDCl₃):

=0.80-1.02 (6H), 1.28-1.55 (12H), 3.78 (1H), 4.64 (1H), 6.52-6.66 (1H),6.98 (1H), 7.01-7.13 (1H), 7.22-7.38 (1H).

(2S)-2-Amino-1-(3-fluorophenyl)-4-methyl-pentane-1-ol hydrochloride

The aforementioned described{(S)-1-[(3-fluorophenyl)-hydroxymethyl]-3-methylbutyl}-carbamic acidtert.-butylester (4.7 g, 15.1 mmol) is dissolved in dioxane (37 mL).After addition of HCl in dioxane (37.7 mL of a 4M solution) the reactionmixture is stirred for 4 h. After evaporation of the solvent the crudeproduct (3.7 g, 99.5%) is used in the next step without furtherpurification.

(2S)-2-Amino-1-(3-fluorophenyl)-4-methyl-pentane-1-ol

(2S)-2-Amino-1-(3-fluorophenyl)-4-methyl-pentane-1-ol hydrochloride (1.6g, 6.46 mmol) is stirred overnight in a mixture of 1N NaOH (12.92 mL)and ethyl acetate (20 mL). The organic phase is separated and theaqueous phase is washed twice with ethyl acetate. The combined organicextracts are washed with brine, dried over Na₂SO₄ and the solvent isevaporated. After purification of the residue by chromatography(silicagel, eluents: dichloromethane/methanol) 694 mg (50.9%) of thetitle compound as mixture of stereoisomers is obtained.

MS (CI+): 212 (M+)

¹H-NMR (300 MHz, CDCl₃):

=0.80-1.08 (6H), 1.20-1.35 (2H), 1.62-1.88 (1H), 1.90-2.55 (broad, 2H),2.96 and 3.16 (combined 1H), 4.33 and 4.63 (combined 1H), 7.02 (1H),7.08-7.20 (2H), 7.29-7.41 (1H).

(αS)-3-Fluoro-β-[[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-α-(2-methylpropyl)benzeneethanamine

(2S)-2-Amino-1-(3-fluorophenyl)-4-methyl-pentane-1-ol (350 mg, 1.66mmol), 5-iodo-1-(4-fluorophenyl)-1H-indazole (672.2 mg, 1.99 mmol),cesiumcarbonate (1.08 g, 3.31 mmol), copper (I)-iodide (157.8 mg, 0.83mmol) and isobutyronitrile (1.75 mL) are stirred in a glass pressuretube at 120° C. for 20 h. The reaction mixture is filtered via a glassmicrofibre filter, the solvent evaporated and the residue purified bychromatography (silicagel, eluents: ethylacetate/methanol). 162.8 mg(23.3%) of the title compound are obtained.

MS (EI+): 421 (M)

¹H-NMR (300 MHz, CDCl₃):

=0.75-1.02 (6H), 1.25-1.90 (3H), 3.18 (broad, 1H), 4.95 (broad, 1H),6.88-7.40 (8H), 7.53 (1H), 7.55-7.70 (2H), 7.99 (1H).

N-{(1S)-1-[(R)-(3-Fluorophenyl)-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}methyl}-3-methyl-butyl}-2-methoxyacetamide

(αS)-3-Fluoro-β-[[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-α-(2-methylpropyl)benzeneethanamine(76.4 mg, 0.18 mmol) is dissolved in 7 mL dichloromethane. Triethylamine(0.06 mL, 0.44 mmol) and 2-methoxyacetyl chloride (0.02 mL, 0.22 mmol)are added. After stirring overnight the reaction mixture is diluted withdichloromethane, washed with water and brine and dried over Na₂SO₄.After filtration the solvent is evaporated and the residue is purifiedby chromatography (silicagel, eluents: ethylacetate/hexane). Theobtained mixture of the two stereoisomers is separated by HPLC(Chiralpak AD-H 5 μm, eluents: hexane/ethanol) yielding 3.7 mg (10.2%)of the title stereoisomer and 24.7 mg (68%) of the stereoisomerN-{(1S)-1-[(S)-(3-fluorophenyl)-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}methyl}-3-methyl-butyl}-2-methoxyacetamide.

MS (EI+): 421 (M)

¹H-NMR (300 MHz, CDCl₃):

=0.79 (3H), 0.93 (3H), 1.16-1.34 (2H), 1.55-1.76 (1H), 3.38 (3H),3.79-3.98 (2H), 4.45 (1H), 5.39 (1H), 6.70 (1H), 6.93 (1H), 7.00 (1H),7.09-7.40 (6H), 7.55 (1H), 7.58-7.69 (2H), 7.98 (1H).

Example 1102,2,2-Trifluoro-N-{(1S)-1-[(R)-(3-Fluorophenyl)-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}methyl}-3-methylbutyl}-acetamide

(αS)-3-Fluoro-β-[[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-α-(2-methylpropyl)benzeneethanaminedescribed in Example 1 (76.4 mg, 0.18 mmol) is dissolved in 7 mLdichloromethane. Triethylamine (0.06 mL, 0.44 mmol) andtrifluoroacetanhydride (0.03 mL, 0.22 mmol) are added. The reactionmixture is stirred overnight and then diluted with dichloromethane,washed with water and brine and dried over Na₂SO₄. After filtration thesolvent is evaporated and the residue is purified by chromatography(silicagel, eluents: ethyl acetate/hexane). The obtained mixture of thetwo stereoisomers is separated by HPLC (Chiralcel OJ-H 5μ, eluents:hexane/ethanol) yielding 3.8 mg (18.3%) of the title stereoisomer and14.2 mg (68%) of the stereoisomer2,2,2-trifluoro-N-{(1S)-1-[(S)-(3-fluorophenyl)-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}methyl}-3-methylbutyl}-acetamide.

MS (EI+): 517 (M)

¹H-NMR (400 MHz, CDCl₃):

=0.81 (3H), 0.93 (3H), 1.23-1.39 (2H), 1.65-1.77 (1H), 4.49 (1H), 5.39(1H), 6.41 (1H), 6.94 (1H), 7.04 (1H), 7.08-7.30 (5H), 7.39 (1H), 7.56(1H), 7.59-7.68 (2H), 7.99 (1H).

Example 111N-[(1)-(2R)-(3-Fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-(methoxymethyl)ethyl]-2-methoxyacetamide

(αS)-3-Fluoro-β-[[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-α-(methoxymethyl])benzeneethanamineis synthesized in analogy to the sequence described in example 1:commercially available Boc-Ser(Me)-OH is transformed into itsWeinreb-amide. Reduction to the aldehyde with LiAlH, followed byreaction with 3-fluorophenylgrignard, cleavage of the protecting group,liberation of the amine from the hydrochloride and etherification with1-(4-fluorophenyl)-5-iodo-1H-indazole. This amine (66.4 mg, 0.16 mmol)is dissolved in 7 mL of dichloromethane. Triethylamine (0.054 mL, 0.39mmol) and 0.018 mL (0.19 mmol) 2-methoxyacetylchloride are added. Thereaction mixture is stirred for four h at r.t. and then diluted withdichloromethane, washed with water and brine and dried over Na₂SO₄.After filtration the solvent is evaporated and the residue purified bychromatography (silicagel, eluents: ethyl acetate/hexane). The mixtureof stereoisomers is separated by HPLC (Chiralpak AD-H 5μ, eluents:hexane/ethanol) providing 3 mg (3.8%) of the title compound and 6 mg(7.6%) of the stereoisomerN-[(1S)-(2S)-(3-fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-(methoxymethyl)ethyl]-2-methoxyacetamide.

MS (CI+): 482 (M+)

¹H-NMR (400 MHz, CDCl₃):

=3.32-3.42 (1H), 3.38 (3H), 3.41 (3H), 3.53-3.62 (1H), 3.78-3.98 (2H),4.57 (1H), 5.52 (1H), 6.94-7.02 (2H), 7.06 (1H), 7.10-7.25 (5H),7.29-7.38 (1H), 7.57 (1H), 7.59-7.68 (2H), 8.01 (1H).

Example 112N-[(1S)-(2R)-(3-Fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(methoxymethyl)ethyl]furan-2-carboxamide

(αS)-3-Fluoro-β-[[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-α-(methoxymethyl)]benzeneethanamine(66.4 mg, 0.16 mmol) is dissolved in 7 mL of dichloromethane.Triethylamine (0.054 mL, 0.39 mmol) and 25 mg (0.19 mmol)2-furoylchloride are added. The reaction mixture is stirred for 4 h atr.t., diluted with dichloromethane, washed with water and brine anddried over Na₂SO₄. After filtration the solvent is evaporated and theresidue purified by chromatography (silicagel, eluents: ethylacetate/hexane). The mixture of stereoisomers is separated by HPLC(Chiralpak AD-H 5μ, eluents: hexane/ethanol) providing 5 mg (6.1%) ofthe title compound and 2 mg (2.5%) of the stereoisomerN-[(1S)-(2S)-(3-fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-(methoxymethyl)ethyl]furan-2-carboxamide.

MS (CI+): 504 (M+)

¹H-NMR (400 MHz, CDCl₃):

=3.38 (3H), 3.42-3.51 (1H), 3.60-3.69 (1H), 4.69 (1H), 5.58 (1H), 6.51(1H), 6.83 (1H), 6.91-7.39 (9H), 7.48 (1H), 7.55 (1H), 7.59-7.69 (2H),8.01 (1H).

Example 113N-[(1S)-2-(3-Fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(hydroxymethyl)ethyl]-2-methoxyacetamide

N-[(1S)-2-(3-Fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-(benzyloxymethyl)ethyl]-2-methoxyacetamide

(αS)-3-Fluoro-β-[[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-α-[(phenylmethoxy)methyl]benzeneethanamineis synthesized in analogy to the sequence previously described inexample 1: commercially available Boc-Ser(Bn)-OH is transformed into itsWeinreb-amide. Reduction to the aldehyde with LiAl₄, reaction with3-fluorophenylgrignard, cleavage of the tert.-butyloxycarbonylprotecting group, liberation of the amine from the hydrochloride andetherification with 1-(4-fluorophenyl)-5-iodo-1H-indazole gives thedesired amine. This amine (123.3 mg, 0.25 mmol) is dissolved in 10 mL ofdichloromethane. Triethylamine (0.084 mL, 0.61 mmol) and 0.028 mL (0.3mmol) 2-methoxyacetylchloride are added. The reaction mixture is stirredovernight at r.t., then diluted with dichloromethane, washed with waterand brine and dried over Na₂SO₄. After filtration the solvent isevaporated and the residue purified by chromatography (silicagel,eluents: ethyl acetate/hexane). 79.1 mg (55.9%) of the title compound asa mixture of stereoisomers are isolated.

MS (CI+): 559 (M+)

¹H-NMR (300 MHz, CDCl₃):

=3.40 and 3.43 (combined 3H), 3.49-3.61 (1H), 3.65-3.78 (1H), 3.79-4.00(2H), 4.49-4.73 (3H), 5.48 and 5.61 (combined 1H), 6.95-7.43 (14H), 7.58(1H), 7.62-7.73 (2H), 8.04 (1H).

N-[(1S)-2-(3-Fluorophenyl)-2-{([1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-(hydroxymethyl)ethyl]-2-methoxyacetamide

N-[(1S)-2-(3-Fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-(benzyloxymethyl)ethyl]-2-methoxyacetamide(15 mg, 0.027 mmol) is dissolved in 10 mL ethanol and Pd (10% oncharcoal, 0.29 mg, 0.0027 mmol) is added. The reaction mixture ischarged with hydrogen and stirred for 2 h at r.t. After filtration ofthe reaction mixture via a glass microfibre filter, the solventevaporated and the residue purified by chromatography (silicagel,eluents: ethylacetate/hexane). 7.5 mg (59.6%) of the title compound as amixture of stereoisomers are obtained.

MS (CI+): 468 (M+)

¹H-NMR (300 MHz, CDCl₃):

=2.20 (broad, 1H), 3.41 and 3.45 (combined 3H), 3.70-4.03 and 4.05-4.21(combined 4H), 4.31-4.47 (1H), 5.57-5.65 (1H), 6.99-7.12 (2H), 7.13-7.47(7H), 7.53-7.71 (3H), 8.04 (1H).

Example 114N-[(1S,2R)-1-Methyl-2-phenyl-2-{[1-(3-pyridyl)-1H-indazol-5-yl]oxy}ethyl]furan-2-carboxamide

5-Iodo-1-(3-pyridyl)-1H-indazole

Cesiumcarbonate (26.84 g, 82.38 mmol) is added to a suspension of2-fluoro-5-iodobenzaldehyde (6.87 g, 27.46 mmol) and 3-pyridylhydrazinedihydrochloride (5 g, 27.46 mmol) in 136 mL N-methylpyrrolidon. Thereaction mixture is stirred overnight at r.t. After checking that thehydrazone has been formed (¹H-NMR) the reaction mixture is heated for 4h at 160° C. The reaction mixture is allowed to cool down and the darkbrown suspension is poured on 1000 mL ice water. After vigorouslystirring at r.t. for 45 min, the precipitated product is sucked off viaa glass microfibre filter, washed with water and dried at the evaporatorat 45° C. 8.28 g (93.9%) of the title compound are obtained.

MS (CI+): 322 (M+)

¹H-NMR (400 MHz, DMSO [d6]):

=7.62 (1H), 7.72 (2H), 8.20 (1H), 8.32 (1H), 8.49 (1H), 8.61 (1H), 9.01(1H).

(αS,βR)-β-{[1-(3-Pyridyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine

(1R,2S)-Norephedrine (500 mg, 3.31 mmol),5-iodo-1-(3-pyridyl)-1H-indazole (1.08 g, 33.37 mmol), cesiumcarbonate(2.15 g, 6.61 mmol), copper (I)-iodide (314.9 mg, 1.65 mmol) andbutyronitrile (2 mL) are stirred in a glass pressure tube at 120° C. for20 h. The reaction mixture is filtered via a glass microfibre filter,the solvent evaporated and the residue purified by chromatography(silicagel, eluents: dichloromethane/methanol). 307.8 mg (27%) of thetitle compound are obtained.

MS (CI+): 345 (M+)

¹H-NMR (300 MHz, CDCl₃):

=1.27 (3H), 3.52 (1H), 5.05 (1H), 7.08 (1H), 7.15-7.60 (7H), 7.68 (1H),7.99-8.12 (2H), 8.62 (1H), 9.08 (1H).

N-[(1S,2R)-1-Methyl-2-phenyl-2-{[1-(3-pyridyl)-1H-indazole-5-yl]oxy}ethyl]furan-2-carboxamide(αS,βR)-β-{[1-(3-Pyridyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine

(75 mg, 0.22 mmol) is dissolved in 8 mL of dichloromethane.Triethylamine (0.072 mL, 0.52 mmol) and 2-furoylchloride (28.4 mg, 0.22mmol) are added. After 4 h stirring at r.t. the reaction mixture isdiluted with dichloromethane, washed with water and brine and dried overNa₂SO₄. The reaction mixture is filtered, the solvent evaporated and theresidue purified by chromatography (silicagel, eluents: ethylacetate/hexane). 46.4 mg (48.6%) of the title compound are obtained.

MS (CI+): 439 (M+)

¹H-NMR (300 MHz, CDCl₃):

=1.29 (3H), 4.62 (1H), 5.51 (1H), 6.51 (1H), 6.78 (1H), 6.99 (1H), 7.13(1H), 7.19-7.54 (8H), 7.63 (1H), 7.96-8.08 (2H), 8.59 (1H), 9.03 (1H).

Example 115N-[(1S,2R)-1-Methyl-2-phenyl-2-{[1-(4-pyridyl)-1H-indazol-5-yl]oxy}ethyl]furan-2-carboxamide

5-Iodo-1-(4-pyridyl)-1H-indazole

Cesiumcarbonate (26.84 g, 82.38 mmol) is added to a suspension of2-fluoro-5-iodobenzaldehyde (6.87 g, 27.46 mmol) and 4-pyridylhydrazinedihydrochloride (5 g, 27.46 mmol) in 136 mL N-methylpyrrolidon. Thereaction mixture is stirred overnight at r.t. After checking that thehydrazone has been formed (¹H-NMR) the reaction mixture is heated for 4h at 160° C. The reaction mixture is allowed to cool down and thedarkbrown suspension is poured on 1000 mL ice water. After vigorouslystirring at r.t. for 45 min, the precipitated product is sucked off viaa glass microfibre filter, washed with water and dried at the evaporatorat 45° C. The title compound is obtained with a yield of 92.3% (8.14 g).

¹H-NMR (300 MHz, DMSO [d6]):

=7.83 (1H), 7.89-7.92 (2H), 7.99 (1H), 8.39 (1H), 8.48 (1H), 8.70-8.78(2H).

(αS,8R)-β-{[1-(4-Pyridyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine

(1R,2S)-Norephedrine (500 mg, 3.31 mmol),5-iodo-1-(4-pyridyl)-1H-indazole (1.08 g, 3.37 mmol), cesiumcarbonate(2.15 g, 6.61 mmol), copper (I)-iodide (314.9 mg, 1.65 mmol) andbutyronitrile (2 mL) are stirred in a glass pressure tube at 120° C. for20 h. The reaction mixture is filtered via a glass microfibre filter,the solvent evaporated and the residue purified by chromatography(silicagel, eluents: dichloromethane/methanol). 257.2 mg (22.6%) of thetitle compound are obtained.

MS (CI+): 345 (M+)

¹H-NMR (300 MHz, CDCl₃):

=1.29 (3H), 3.45 (1H), 5.08 (1H), 7.05 (1H), 7.18-7.50 (6H), 7.62-7.83(3H), 8.08 (1H), 8.63-8.82 (2H).

N-[(1S,2R)-1-Methyl-2-phenyl-2-{[1-(4-pyridyl)-1H-indazole-5-yl]oxy}ethyl]furan-2-carboxamide

(αS,βR)-β{[1-(4-Pyridyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine(64.3 mg, 0.19 mmol) is dissolved in 7.1 mL of dichloromethane.Triethylamine (0.062 mL, 0.45 mmol) and 2-furoylchloride (24.3 mg, 0.19mmol) are added. After 4 h stirring at r.t. the reaction mixture isdiluted with dichloromethane, washed with water and brine and dried overNa₂SO₄. The reaction mixture is filtered, the solvent evaporated and theresidue purified by chromatography (silicagel, eluents: ethylacetate/hexane). 53.7 mg (65.6%) of the title compound are obtained.

MS (CI+): 439 (M+)

¹H-NMR (300 MHz, CDCl₃):

=1.29 (3H), 4.62 (1H), 5.52 (1H), 6.50 (1H), 6.75 (1H), 7.00 (1H), 7.13(1H), 7.19-7.50 (8H), 7.65-7.82 (3H), 8.02 (1H), 8.72 (1H).

Example 116 Methyl4-(5-{(1R,2S)-2-[(2-furylcarbonyl)amino]-1-phenylpropoxy}-1H-indazol-1-yl)benzoate

Methyl-4-(5-iodoindazole-1-yl)-benzoate

4-Hydrazinobenzoic acid (11.32 g, 60 mmol) and cesiumcarbonate (58.65 g,180 mmol) are added to 2-fluoro-5-iodobenzaldehyde (15 g, 60 mmol) in300 mL N-methylpyrrolidon. After 1 h stirring at r.t., the reaction isheated for 4 h at 150° C. The reaction mixture is allowed to cool offand poured on 1 L ice water. The reaction mixture is acidified withcitric acid and vigorously stirred at r.t. for 30 min. The precipitateis filtered off and given in ethyl acetate. The slurry is vigorouslystirred for 1 h and sucked off. The filter residue (few material) isdiscarded and the filtrate evaporated. This residue which iscontaminated with N-methylpyrrolidine is treated with 300 mL of amixture of ethyl acetate/hexane (1:3) and stirred overnight. Theprecipitated crystals are sucked off and dried. 17.11 g (78.32%) of4-(5-iodoindazole-1-yl)-benzoic acid are obtained.

K₂CO₃ (7.35 g, 53.2 mmol) is suspended in 110 mL DMF.4-(5-iodoindazole-1-yl)-benzoic acid (17.6 g, 48.33 mmol), dissolved in25 mL DMF, is added dropwise. The reaction mixture is stirred for 30 minat r.t. Subsequently CH₃I (3.31 mL, 53.2 mmol) is added dropwise(temperature rises to 30° C.). The reaction mixture is stirred overnightat r.t. and then poured on ice water. It is three times extracted withethyl acetate. The combined organic extracts are washed twice with waterand brine. After drying over Na₂SO₄ and filtration the solvent isevaporated. The residue is purified by chromatography (silicagel,eluents: ethyl acetate/hexane) yielding 14.03 g (76.8%) of the titlecompound.

MS (CI+): 496 (M+)

¹H-NMR (300 MHz, DMSO [d6]):

=3.92 (3H), 7.75-7.92 (2H), 7.93-8.03 (2H), 8.10-8.25 (2H), 8.38 (1H),8.44 (1H).

Methyl 4-{5-[(1R,2S)-2-amino-1-phenylpropoxy]-1H-indazole-1-yl}benzoate

(1R,2S)-Norephedrine (500 mg, 3.31 mmol),methyl-4-(5-iodoindazole-1-yl)-benzoate (1.28 g, 3.37 mmol),cesiumcarbonate (2.15 g, 6.61 mmol), copper (I)-iodide (314.9 mg, 1.65mmol) and butyronitrile (2 mL) are stirred in a glass pressure tube at120° C. for 20 h. The reaction mixture is filtered via a glassmicrofibre filter, the solvent evaporated and the residue purified bychromatography (silicagel, eluents: dichloromethane/methanol). 217.9 mg(16.4%) of the title compound are obtained.

MS (CI+): 402 (M+)

¹H-NMR (300 MHz, CDCl₃):

=1.29 (3H), 4.00 (3H), 5.05 (1H), 5.42 (1H), 7.04 (1H), 7.23 (1H),7.28-7.55 (5H), 7.22 (1H), 7.78-7.90 (2H), 8.08 (1H), 8.18-8.30 (2H).

Methyl4-(5-{(1R,2S)-2-[(2-furylcarbonyl)amino]-1-phenylpropoxy}-1H-indazole-1-yl)benzoate

Methyl 4-{5-[(1R,2S)-2-amino-1-phenylpropoxy]-1H-indazole-1-yl}benzoate(64.3 mg, 0.16 mmol) is dissolved in 6.1 mL of dichloromethane.Triethylamine (0.053 mL, 0.38 mmol) and 2-furoylchloride (20.9 mg, 0.16mmol) are added. After 4 h stirring at r.t. the reaction mixture isdiluted with dichloromethane, washed with water and brine and dried overNa₂SO₄. The reaction mixture is filtered, the solvent evaporated and theresidue purified by chromatography (silicagel, eluents: ethylacetate/hexane). 38.2 mg (48.1%) of the title compound are obtained.

MS (CI+): 496 (M+)

¹H-NMR (300 MHz, CDCl₃):

=1.32 (3H), 4.01 (3H), 4.69 (1H), 5.58 (1H), 6.53 (1H), 6.79 (1H), 7.04(1H), 7.19 (1H), 7.23-7.55 (7H), 7.75 (1H), 7.79-7.89 (2H), 8.06 (1H),8.19-8.29 (2H).

Example 117N-{(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenylpropan-2-yl}-5-methyl-[1,3,4]oxadiazol-2-carboxamide

To a stirred solution of HATU (630 mg, 1.66 mmol) in DMF (1 ml) wasadded ethyldiisopropylamine (570 μl, 3.3 mmol), followed by5-methyl-[1,3,4]oxadiazol carboxylic acid potassium salt (138 mg, 830μmol) and stirred for 20 min. Then(1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine(300 mg, 830 mmol) in DMF (1 ml) was added to the brown/red solution andthe stirring was continued for 24 h at r.t. The mixture was diluted bydichloromethane and filtrated through a path of silica gel. Solvent wasremoved under reduced pressure, and the residue was purified bypreparative TLC on silica gel (hexane/acetone 50%). Yield 82 mg (21%).

ES⁺-MS: m/z=472 [MH⁺]

¹H-NMR (300 MHz, CDCl₃) δ=7.95 (d, 1H), 7.62 (dd, 2H), 7.55 (d, 1H),7.46-7.32 (m, 6H), 7.21 (dd, 2H), 7.18 (d, 1H), 6.95 (d, 1H), 5.46 (d,1H), 4.63 (ddq, 1H), 2.62 (s, 3H), 1.30 (d, 3H).

Example 1182-Methoxy-N-[1-methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethyl]acetamide

1-Methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethylamine(118a, 14 mg, 0.041 mmol), DIPEA (12 ul, 0.070 mmol) and acetonitrile (2ml) were charged in a 7 ml vial. Methoxyacetyl chloride (12 ul, 0.13mmol) was added, the vial was sealed and the solution stirred (magneticbar) at r.t. for 1 h. Concentration and purification on C18 (Kromasil)with acetonitrile:water:TFA, 45:55:0.1 to 90:10:0.1 over 30 min,afforded 5 mg (29%) of2-methoxy-N-[1-methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethyl]acetamide.

APCI-MS ^(m)/z: 417.1 [MH⁺]

¹H NMR (300 MHz, (CD₃)₂CO) δ 8.58 (bs, 1H), 8.51-8.37 (m, 1H), 8.17-7.87(m, 3H), 7.40 (s, 1H), 7.42-7.35 (m, 4H) 7.35-7.22 (m, 3H), 6.97 (s,1H), 5.39 (d, 1H), 4.57-4.47 (m, 1H), 4.01 (q, 2H), 3.40 (s, 3H), 1.24(d, 3H)

1-Methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethylamine(118a)

5-Iodo-1-pyridin-2-yl-1H-indazole (118b, 81 mg, 0.25 mmol),(1R,2S)-(−)-norephedrine (119 mg, 0.79 mmol) and butyronitrile (3 ml)were charged in a 7 ml vial. Copper(I) iodide (5.8 mg, 0.1 mol %) andcesium carbonate (261 mg, 0.8 mmol) were added, the vial was sealed andthe solution was stirred (magnetic bar) at 125° C. for 2 h. Inorganicmaterial was filtered off, and washed with ethyl acetate. The ethylacetate phase was collected and concentrated and purified on silica withmethanol:ethyl acetate 0:100 to 30:70 over 45 min. Pure fractions werepooled and concentrated to give 14 mg (16%) of1-methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethylamine.

APCI-MS ^(m)/z: 345.1 [MH⁺]

5-Iodo-1-pyridin-2-yl-1H-indazole (118b)

2-Fluoro-5-iodobenzaldehyde (527 mg, 2.11 mmol), 2-hydrazinopyridine(237 mg, 2.17 mmol), cesium carbonate (2.06 g, 6.32 mmol) and NMP (10ml) werer charged in a 10 ml vial which was sealed and stirred (magneticbar) over night at 100° C. Water and ethylacetate were added and thephases was separated. The organic layer was washed three times withbrine and concentrated. Purification on silica with ethylacetate:heptane5:95 to 10:90 over 15 min, 10 ml/min, followed by evaporation afforded31 mg (5%) of 5-iodo-1-pyridin-2-yl-1H-indazole.

APCI-MS ^(m)/z: 321.8 [MH⁺]

¹H NMR (300 MHz, CDCl₂) δ 8.64 (dt, 1H), 8.50 (dq, 1H), 8.13 (dd, 1H),8.11 (d, 1H), 7.87-7.81 (m, 1H), 7.74 (dd, 1H).

Example 119N-{2-[1-(6-Chloro-pyridazin-3-yl)-1H-indazol-5-yloxy]-1-methyl-2-phenyl-ethyl}-2,2,2-trifluoro-acetamide

2-[1-(6-Chloro-pyridazin-3-yl)-1H-indazol-5-yloxy]-1-methyl-2-phenyl-ethylamine(119a, 29 mg, 0.076 mmol), trifluoroacetic anhydride (185 ul, 1.31mmol), triethylamine (25 ul, 0.18 mmol) and dichloromethane (3 ml) werecharged in a 7 ml vial. The vial was sealed and the solution stirred(magnetic bar) at r.t. for 18 h. Concentration and purification on C18(Kromasil) with acetonitrile:water, 32:68 to 75:25 over 30 min, afforded12 mg (33%) ofN-{2-[1-(6-Chloro-pyridazin-3-yl)-1H-indazol-5-yloxy]-1-methyl-2-phenyl-ethyl}-2,2,2-trifluoro-acetamide.

APCI-MS ^(m)/z: 475.9 [MH⁺]

¹H NMR (300 MHz, (CD₃CN) δ 8.59 (dt, 1H), 8.20 (d, 1H), 8.12 (d, 1H),7.70 (d, 1H), 7.66 (bd, 1H) 7.45-7.25 (m, 6H), 7.10 (d, 1H), 5.39 (d,1H), 4.46-4.32 (m, 1H), 1.31 (d, 3H).

2-[1-(6-Chloro-pyridazin-3-yl)-1H-indazol-5-yloxy]-1-methyl-2-phenyl-ethylamine(119a)

Prepared as described for 118a using1-(6-Chloro-pyridazin-3-yl)-5-iodo-1H-indazole (119b). Yield 35 mg (7%).

APCI-MS ^(m)/z: 380.1 [MH⁺]

1-(6-Chloro-pyridazin-3-yl)-5-iodo-1H-indazole (119b)

Prepared as described for 118b using 3-chloro-6-hydrazinopyridazine.Yield 687 mg (45%).

¹H NMR (300 MHz, (CD₃)₂SO) δ 8.55 (s, 1H), 8.49 (d, 1H), 8.37 (d, 1H),8.34 (d, 1H), 8.08 (d, 1H), 7.93 (dd, 1H).

APCI-MS ^(m)/z: 356.8 (MH⁺)

Example 1202-Methoxy-N-[1-methyl-2-phenyl-2-(1-pyrimidin-2-yl-1H-indazol-5-yloxy)-ethyl]-acetamide

Prepared as in Example 118 using1-methyl-2-phenyl-2-(1-pyrimidin-2-yl-1H-indazol-5-yloxy)-ethylamine(120a). Yield 7 mg (9%).

APCI-MS ^(m)/z: 418.0 [MH+]

¹H NMR (300 MHz, (CD₃CN) δ 8.80 (d, 2H), 8.61 (d, 1H), 8.10 (s, 1H),7.47-7.24 (m, 7H), 7.11 (d, 1H), 6.91 (bd, 1H), 5.41 (d, 1H), 4.45-4.35(m, 1H), 3.75 (q, 2H), 3.29 (s, 3H), 1.23 (d, 3H).

1-Methyl-2-phenyl-2-(1-pyrimidin-2-yl-1H-indazol-5-yloxy)-ethylamine(120a)

Prepared as described for 118a using 5-Iodo-1-pyrimidin-2-yl-1H-indazole(120b). Yield 66 mg (20%).

APCI-MS ^(m)/z: 346.0 (MH⁺)

5-Iodo-1-pyrimidin-2-yl-1H-indazole (120b)

Prepared as described for 118b using 2-hydrazinopyrimidine. Yield 296 mg(24%).

APCI-MS ^(m)/z: 322.9 [MH+]

¹H NMR (300 MHz, (CD₃)₂SO) δ 8.94 (d, 2H), 8.50 (dt, 1H), 8.44 (d, 1H),8.33 (dd, 1H), 7.87 (dd, 1H), 7.47 (t, 1H).

Example 121N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2-hydroxy-acetamide

The title compound was prepared analogous to the method described inExample 21 starting from(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a) (511 mg, 1.31 mmol), and Acetoxyacetyl chloride (155 μL, 1.44mmol). Yield 429 mg (73%).

APCI-MS: m/z 450.1 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.17 (d, 1H), 7.78-7.67 (m, 3H), 7.62 (d,1H), 7.40 (t, 2H), 7.27 (t, 1H), 7.22 (dd, 1H), 7.11 (d, 1H), 7.00-6.94(m, 2H), 6.83 (dd, 1H), 5.51 (t, 1H), 5.39 (d, J=5.04 Hz, 1H), 4.25 (m,1H), 3.75 (m, 2H), 3.73 (s, 3H), 1.18 (d, 3H) ppm.

Example 1222,2,2-trifluoro-N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(quinolin-3-yl)propan-2-yl)acetamide

(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(quinolin-3-yl)propan-2-aminebis(2,2,2-trifluoroacetate) (65 mg, 0.10 mmol) was dissolved in MeOH(1.5 mL), 1,1,3,3-tetramethylguanidine (0.064 mL, 0.51 mmol) and ethyltrifluoroacetate (0.242 mL, 2.03 mmol) was added, the reaction mixturewas stirred at r.t. for 2.5 h. Solvent was removed by evaporation andthe residual material was purified by HPLC. Fractions was freezedried togive the product as a colourless powder. Yield 35 mg (67%)

APCI-MS: m/z 509.1 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 9.64 (brs, 1H), 8.96 (d, 1H), 8.35 (d, 1H),8.14 (d, 1H), 7.98 (m, 2H), 7.79-7.66 (m, 4H), 7.60 (m, 1H), 7.38 (m,2H), 7.27 (m, 2H), 5.56 (d, 1H), 4.45 (m, 1H), 1.42 (d, 3H)(1R,2S)-1-(1-(4-fluorophenva-1H-indazol-5-yloxy)-1-(quinolin-3-propan-2-aminebis(2,2,2-trifluoroacetate) (122a)

Following the procedure described in Example 19 (step 19a). Startingfrom (1R,2S)-2-amino-1-(quinolin-3-yl)propan-1-ol dihydrochloride (250mg, 0.80 mmol), 1-(4-fluorophenyl)-5-iodo-1H-indazole (340 mg, 1.01mmol), Cs₂CO₃ (1070 mg, 3.28 mmol) and CuI (36 mg, 0.19 mmol) inbutyronitrile (4 mL), the reaction vessel was sealed and flushed withargon, the resulting slurry was stirred at +125° C. for 5 h, thetemperature was then lowered to 100° C. and the mixture was stirred overnight 16 h. Workup and purification by HPLC afforded the subtitlecompound as a hygroscopic yellow powder. Yield 200 mg (39%)

APCI-MS m/z: 413.1 [MH⁺-2TFA]

¹H-NMR (300 Mhz, DMSO-d6): δ 9.01 (d, 1H), 8.41 (d, 1H), 8.26 (brs, 3H),8.17 (d, 1H), 8.02 (t, 2H), 7.84-7.68 (m, 4H), 7.64 (m, 1H), 7.44-7.34(m, 3H), 7.28 (d, 1H), 5.89 (d, J=3.32 Hz, 1H), 3.95 (m, 1H), 1.26 (d,3H)

(1R,2S)-2-amino-1-(quinolin-3-yl)propan-1-ol dihydrochloride (122b)

Following the procedure described in Example 19 (step 19b+19c). Startingfrom (S)-tert-butyl 1-oxo-1-(quinolin-3-yl)propan-2-ylcarbamate (1.6 g,5.33 mmol), Aluminum isopropoxide (0.68 g, 3.33 mmol) and 2-propanol(4.5 mL, 59.16 mmol) in toluene (7 mL) stirred at +50° C. in sealedreaction tube flushed with argon for 16 h. Work up and deprotection ofthe intermediate BOC-protected amine afforded the subtitle compound as acolourless solid.

Yield 1.29 g (88%).

APCI-MS m/z: 203 [MH⁺-2HCl]

¹H-NMR (400 Mhz, DMSO-d6): δ 9.23 (d, 1R), 8.97 (s, 1H), 8.42-8.24 (m,5H), 8.06 (t, 1H), 7.89 (t, 1H), 6.68 (vbrs, 1H), 5.28 (d, J=3.72 Hz,1H), 3.68 (m, 1H), 1.10 (d, 3H)

(S)-tert-butyl 1-oxo-1-(quinolin-3-yl)propan-2-ylcarbamate (122c)

(S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (2.5g, 10.76 mmol) was suspended in THF (5 mL) and stirred at −10° C.,isopropylmagnesium chloride 2.0M solution in THF (5.4 ml, 10.80 mmol)was added and a solution was formed. To this solution was added asolution of Lithium tri(3-quinolinyl)magnesiate in THF/Hexane, preparedfrom 3-bromoquinoline (1.471 ml, 10.81 mmol) according to the proceduredescribed by Sylvain Dumouchel et-al. in Tetrahedron 59 (2003)8629-8640. The mixture was stirred at −10° C. for 30 min and was theallowed to reach r.t. and stirred over night, 15 h. The reactionmixture, a clear red solution, was slowly poured into ice-cooled 1M HCl(aq) (100 mL). EtOAc (150 mL) was added and the mixture was stirred fora few min, the water phase was extracted once with EtOAc, the combinedEtOAc solutions was further washed with saturated NaHCO₃ (aq) and brine.The crude material was purified by flash-chromatography on silica usinga gradient of 0% to 40% EtOAc in Heptane. The obtained material was thefurther purified by HPLC to afford the subtitle compound as a yellowsticky oil. Yield 1.6 g (49%)

APCI-MS m/z: 301.1 [MH⁺]

¹H-NMR (400 Mhz, CDCl₃): δ 9.44 (d, 1H), 8.81 (s, 1H), 8.20 (d, 1H),7.98 (d, 1H), 7.89 (t, 1H), 7.67 (t, 1H), 5.53 (brd, 1H), 5.42 (m, 1H),1.48 (d, 3H), 1.47 (s, 9H)

Example 123N-((1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-yl)-2-hydroxyacetamide

(1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine2,2,2-trifluoroacetate. (19a) (0.16 g, 0.30 mmol) andN,N-diisopropylethylamine (0.16 mL, 0.92 mmol) in THF (3 mL) was treatedwith acetoxyacetyl chloride (0.04 mL, 0.37 mmol). The mixture wasstirred at ambient temperature for 1 h. LC/MS showed formation ofintermediate hydroxyacetyl compound, MH+=520, no unreacted amineremained. To the reaction mixture was added water (1 mL), 28% ammoniasolution in water (1 mL) and MeOH (0.5 mL. The mixture was stirred atr.t. over night. The solvents was removed by evaporation and theresidual material was purified by HPLC. Fractions with product wasfreezedried. Yield 79 mg (55%)

APCI-MS: m/z 478.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 8.18 (d, 1H), 7.74 (m, 2H), 7.69 (d, 1H),7.58 (d, 1H), 7.40 (t, 2H), 7.19 (dd, 1H), 7.11 (d, 1H), 6.89-6.69 (m,3H), 5.51 (t, 1H), 5.32 (d, 1H), 4.19 (m+s, 1H+4H), 3.75 (m, 2H), 1.17(d, 3H)

Example 124N-((1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-yl)-1-methylcyclopropanecarboxamide

1-methylcyclopropanecarboxylic acid (39 mg, 0.39 mmol), HATU (150 mg,0.39 mmol) and DIPEA (170 μl, 0.97 mmol) in NMP (2 mL) was stirred atr.t. for 5 min until a solution had formed. To this solution was added(1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine(19a) (102 mg, 0.24 mmol) dissolved in NMP (1 mL). The reaction mixturewas stirred for 2 h at r.t. The reaction mixture was diluted with water(10 mL) and extracted with EtOAc (2×10 mL), the organic phases was thenwashed with brine, dried over Na2SO4, filtered and evaporated. Theremaining oily residue was purified by HPLC. Fractions containingproduct was freezedried. Yield 68 mg (55%10).

APCI-MS: m/z 502.2 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.19 (d, 1H), 7.79-7.65 (m, 3H), 7.40 (m,2H), 7.27 (d, 1H), 7.18 (dd, 1H), 7.09 (d, 1H), 6.88-6.77 (m, 3H), 5.19(d, 1H), 4.19 (s, 4H), 4.12 (m, 1H), 1.21 (d, 3H), 1.18 (s, 3H), 0.80(m, 2H), 0.41 (m, 2H) ppm.

Example 125(S)-N-((1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-yl)pyrrolidine-2-carboxamide

(1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine(19a) (102 mg, 0.24 mmol) dissolved in NMP (1 mL) was added to asolution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (77mg, 0.36 mmol), HATU (150 mg, 0.39 mmol) and DIPEA (170 μl, 0.97 mmol)in NMP (2 mL). The mixture was stirred at r.t. for 1 h. The reactionmixture was diluted with water (10 mL) and extracted with EtOAc (2×10mL), the organic solution was washed with brine, dried (Na2SO4),filtered and evaporated to give an oily residue. The obtained materialwas dissolved in EtOAc (20 mL) and treated with 5-6N HCl in 2-Propanol(5 mL), the solution was stirred at +40° C. for 1 h. Solvents wasremoved by evaporation. The crude material was purified by HPLC,relevant fractions was freezedried to give the title compound as acolourless solid. Yield 21 mg (16%)

APCI-MS: m/z 517.0 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.18 (d, 1H), 8.02 (d, 1H), 7.74 (m, 2H),7.68 (d, 1H), 7.40 (m, 1H), 7.19 (dd, 1H), 7.13 (d, 1H), 6.88-8.78 (m,3H), 5.28 (d, 1H), 4.19 (s, 4H), 4.10 (m, 1H), 3.43 (m, 1H), 3.20-2.60(vbrs, 1H), 2.73 (m, 2H), 1.85 (m, 1H), 1.52 (m, 3H), 1.13 (d, 3H) ppm.

Example 126N-((1R,2S)-1-(1-(4-chlorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)-2,2,2-trifluoroacetamide

(1R,2S)-1-(1-(4-chlorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(250 mg, 0.61 mmol) was dissolved in THF (5 mL),N,N-diisopropylethylamine (255 μl, 1.54 mmol) was added. Trifluoroaceticanhydride (105 μl, 0.74 mmol) was added and the mixture was stirred atr.t. for 30 min. The reaction mixture was concentrated and the residualmaterial was purified by HPLC, C-18, 50-90% MeCN/water gradient, thepure fractions was combined and freeze dried. Yield: 187 mg (60%).

APCI-MS: m/z 504.1 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 9.51 (brd, 1H), 8.21 (d, 1H), 7.76 (m, 3H),7.61 (m, 2H), 7.29-7.19 (m, 2H), 7.14 (d, 1H), 7.00-6.93 (m, 2H), 6.84(m, 1H), 5.27 (d, 1H), 4.24 (m, 1H), 3.72 (s, 3H), 1.33 (d, 3H) ppm.

(1R,2S)-1-(1-(4-chlorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(126a)

The subtitle compound was prepared analogous to the method described inExample 6 (step 6a). Starting from the hydrochloride salt of(1R,2S)-2-amino-1-(3-methoxyphenyl)propan-1-ol (6b) (0.88 g, 4.04 mmol),1-(4-chlorophenyl)-5-iodo-1H-indazole (1.720 g, 4.85 mmol), CuI (0.154g, 0.81 mmol) and cesium carbonate (3.95 g, 12.13 mmol) in butyronitrile(14 mL) stirred at +110° C. for 16 h. Work up and final purification byHPLC was followed by extraction of product into EtOAc from basic watersolution, evaporation of solvents gave the subtitle compound as a stickyoil. Yield 490 mg (29%)

APCI-MS: m/z 408.1 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.01 (d, 1H), 7.66 (d, 2H), 7.62 (d, 1H),7.53 (d, 2H), 7.27 (t, 1H), 7.23 (dd, 1H), 7.09 (d, 1H), 7.02-6.96 (m,2H), 6.84 (ddd, 1H), 5.10 (d, 1H), 3.76 (s, 3H), 3.27 (m, 1H), 1.20 (d,3H)

1-(4-chlorophenyl)-5-iodo-1H-indazole (126b)

4-chlorophenylhydrazine hydrochloride (5.24 g, 29.27 mmol),2-fluoro-5-iodobenzaldehyde (7.5 g, 30.00 mmol) and cesium carbonate(22.8 g, 69.98 mmol) was suspended in NMP (120 mL) and stirred atambient temperature for 45 min. The temperature was raised to +160° C.and the reaction mixture was stirred for 1 h, the now black suspensionwas allowed to reach r.t. Water was added, the slurry was extracted withEtOAc (500 mL. The organic phase was washed with brine (2×). The brinefractions and waterphase was combined and back extracted once withEtOAc. This second EtOAc phase was washed with brine (2×) beforecombined with the previous EtOAc phase. The organic phases were driedover Na₂SO₄, filtered and evaporated. The black residue were dissolvedin DCM/Heptane (=1/1) and filtered through a silica column, and thecolumn was then further eluted with DCM/Heptane (=1/1) solvent mixture.The fractions containing product was evaporated, residue was dissolvedin EtOAc and Heptane was added, evaporation and diluting with Heptaneafforded a slurry, the solid material was collected by filtration andwashed with Heptane. Yield 2.82 g (27%)

APCI-MS: m/z 354.9 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.36 (d, J=0.79 Hz, 1H), 8.32 (dd, J=0.66Hz, 1.46 Hz, 1H), 7.80 (m, 2H), 7.73 (d, J=1.54 Hz, 1H), 7.71 (t,unresolved, 1H), 7.65 (m, 2H)

Example 127N-((1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-yl)-2,2-difluoropropanamide

(1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine2,2,2-trifluoroacetate. (19a) (316 mg, 0.59 mmol) was partitionedbetween EtOAc and 1M NaOH (aq) solution. The organic phase was washedwith brine, dried (MgSO₄), filtered and evaporated to give 256 mg of thefree amine as a sticky oil. This material was dissolved in NMP (3.5 mL)and added to a stirred solution of 2,2-difluoropropanoic acid (104 mg,0.95 mmol), HATU (360 mg, 0.95 mmol) and DIPEA (0.414 mL, 2.37 mmol) inNMP (1.5 mL). The reaction mixture was stirred at r.t. for 2 h.Additional 2,2-difluoropropanoic acid (80 mg, 0.73 mmol), HATU (278 mg,0.73 mmol) and DIPEA (0.25 mL, 1.4 mmol) in NMP (1.5 mL) was added. Thereaction mixture was stirred at r.t. for one more h. Water (50 mL) wasadded, the mixture was extracted with EtOAc (2×50 mL), the organic phasewas washed with 10% NaHSO₄ (aq), brine, dried over MgSO₄, filtered andevaporated to give a crude product that was purified by HPLC. Thefractions containing the product was combined and freeze dried. Yield155 mg (51%).

APCI-MS: m/z 512.0 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 8.65 (d, J=8.49 Hz, 1H), 8.19 (d, J=0.53Hz, 1H), 7.74 (m, 2H), 7.69 (d, 1H), 7.40 (t, 2H), 7.18 (dd, 1H), 7.11(d, 1H), 6.89-6.78 (m, 3H), 5.16 (d, J=6.72 Hz, 1H), 4.18 (s, 4H), 4.17(m, 1H), 1.55 (t, J=19.46 Hz, 3H), 1.29 (d, J=6.72 Hz, 3H) ppm.

Example 128N-((1R,2S)-1-(1-(4-chlorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide

(1R,2S)-1-(1-(4-chlorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(126a) (256 mg, 0.63 mmol) dissolved in NMP (3.5 mL) was added to asolution of 2,2-difluoropropanoic acid (111 mg, 1.00 mmol), HATU (382mg, 1.00 mmol) and DIPEA (0.438 mL, 2.51 mmol) in NMP (1.5 mL). Thereaction mixture was stirred at r.t. for 2 h. Additional2,2-difluoropropanoic acid (80 mg, 0.73 mmol), HATU (278 mg, 0.73 mmol)and DIPEA (0.25 mL, 1.4 mmol) in NMP (1.5 mL) was added. The reactionmixture was stirred at r.t. for another h. Water (50 mL) was added, themixture was extracted with EtOAc (2×50 mL), the organic phase was washedwith 10% NaHSO4 (aq), brine, dried over MgSO₄, filtered and evaporatedto give a crude product that was purified by HPLC. The fractionscontaining the product was combined and freeze dried. Yield 197 mg(62%).

APCI-MS: m/z 500.3 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 8.69 (d, 1H), 8.21 (d, 1H), 7.76 (d, 3H),7.60 (d, 2H), 7.28-7.19 (m, 2H), 7.13 (d, 1H), 7.00-6.93 (m, 2H), 6.82(dd, 1H), 5.24 (d, 1H), 4.21 (m, 1H), 3.72 (s, 3H), 1.52 (t, 3H), 1.31(d, 3H) ppm.

Example 1292,2,2-Trifluoro-N-[(1R,2S)-1-phenyl-1-(1-propan-2-ylindazol-5-yl)oxy-propan-2-yl]acetamide

The title compound was prepared from(1R,2S)-1-[(1-isopropyl-1H-indazol-5-yl)oxy]-1-phenylpropan-2-amine(129b, 31 mg, 100 μmol) and trifluoroacetic anhydride (63 mg, 300 μmol)as described in Example 1. Yield 28 mg (70%).

APCI-MS: m/z 406 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.57 (d, J=6.7 Hz, 1H), 7.74 (s, 1H),7.49 (dd, J=10.5, 9.1 Hz, 3H), 7.37 (t, J=7.5 Hz, 2H), 7.28 (m, 1H),7.12 (dd, J=9.1, 2.4 Hz, 1H), 7.01 (d, J=2.3 Hz, 1H), 5.44 (d, J=5.0 Hz,1H), 4.88 (septet, J=6.6 Hz, 1H), 4.41 (sextet, J=6.8 Hz, 1H), 1.47 (dd,J=6.5, 3.5 Hz, 6H), 1.37 (d, J=6.9 Hz, 3H).

(1R,2S)-1-[(1-isopropyl-1H-indazol-5-yl)oxy]-1-phenylpropan-2-amine(129b)

A mixture of 5-iodo-1-isopropyl-1H-indazole (129c, 461 mg, 1.26 mmol),(1R,2S)-2-amino-1-phenylpropan-1-ol (286 mg, 1.89 mmol), copper (I)iodide (25 mg, 130 μmol), and cesium carbonate (1.45 g, 3.8 mmol) inbutyronitrile (5 ml) was stirred at 125° C. for 2 h. Then the mixturewas cooled to r.t., the inorganic material was removed by filtration andwashed with ethyl acetate. The combined organic solutions wereconcentrated in vacuo, and the product purified by flash chromatographyon silica gel (ethyl acetate/methanol). Yield 200 mg (51%) of a brownoil.

APCI-MS: m/z 310 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆/D₂O/TFA) δ 7.80 (s, 1H), 7.53 (d, J=9.0 Hz,1H), 7.40 (d, J=7.1 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H), 7.24 (m, 1H), 7.08(dd, J=9.0, 2.3 Hz, 1H), 6.98 (d, J=2.1 Hz, 1H), 5.75 (s, 1H), 5.03 (d,J=5.3 Hz, 1H), 4.86 (septet, J=6.7 Hz, 1H), 3.15 (quintet, J=6.0 Hz,1H), 1.41 (dd, J=6.4, 5.5 Hz, 6H), 1.06 (d, J=6.5 Hz, 3H).

5-Iodo-1-isopropyl-1H-indazole (129c)

A mixture of 5-iodo-1H-indazole (488 mg, 2 mmol), isopropyl bromide (244mg, 2 mmol), and KOtBu (336 mg, 3 mmol) in dry DMF (4 ml) was stirred atr.t. overnight. Then it was dilated with ethyl acetate (50 ml), washedwith water (2×50 ml), and dried with Na₂SO₄. Evaporation of solvent andpurification by flash chromatography on silica gel (n-heptane/ethylacetate) afforded the subtitle compound (298 mg, 52%) along with5-iodo-2-isopropyl-2H-indazole (227 mg, 40%).

APCI-MS: m/z 287 [MH⁺]

¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J=0.9 Hz, 1H), 7.94 (s, 1H), 7.60(dd, J=8.8, 1.5 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 4.83 (septet, J=6.8 Hz,1H), 1.61 (d, J=6.7 Hz, 6H)

Example 130N-[(1R,2S)-1-(1-cyclopentylindazol-5-yl)oxy-1-phenyl-propan-2-yl]-2,2,2-trifluoro-acetamide

The title compound was prepared from(1R,2S)-1-[(1-cyclopentyl-1H-indazol-5-yl)oxy]-1-phenylpropan-2-amine(130b, 17 mg, 51 μmol) and trifluoroacetic anhydride (32 mg, 153 μmol)as described in Example 1. Yield 14 mg (64%).

APCI-MS: m/z 432 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.57 (d, J=7.4 Hz, 1H), 7.73 (s, 1H),7.49 (m, 3H), 7.37 (t, J=7.5 Hz, 2H), 7.28 (t, J=7.3 Hz, 1H), 7.12 (dd,J=9.1, 2.4 Hz, 1H), 7.01 (d, J=2.1 Hz, 1H), 5.44 (d, J=5.0 Hz, 1H), 5.05(quintet, J=7.0 Hz, 1H), 4.41 (sextet, J=6.8 Hz, 1H), 2.07-2.16 (m, 4H,partially covered with the signal of solvent), 1.83-1.93 (m, 2H),1.65-1.76 (m, 2H), 1.37 (d, J=6.9 Hz, 3H).

(1R,2S)-1-[(1-cyclopentyl-1H-indazol-5-yl)oxy]-1-phenylpropan-2-amine(130b)

Prepared from 1-cyclopentyl-5-iodo-1H-indazole (130c, 158 mg, 500 μmol)as described for 129b. Yield 34 mg (20%).

APCI-MS: m/z 336 [MH⁺]

1-Cyclopentyl-5-iodo-1H-indazole (130c)

A mixture of 2-fluoro-5-iodobenzaldehyde (500 mg, 2 mmol),cyclopentylhydrazine (273 mg, 2 mmol), and cesium carbonate (1.91 g, 5mmol) in NMP (5 ml) was stirred at 100° C. overnight. Then KOtBu (560mg, 5 mmol) and DMF (10 ml) were added, and the mixture was stirred at150° C. for 5 h. After cooling to r.t., the mixture was diluted withethyl acetate (100 ml), and washed with water (3×50 ml), and dried.Evaporation of solvent afforded batch residue, which was dissolved inacetonitrile (50 ml), and the insoluble material was removed byfiltration. Flash chromatography on silica gel (n-heptane/ethyl acetate)afforded yellow oil, 158 mg (25%).

APCI-MS: m/z 313 [MH⁺]

¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=0.9 Hz, 1H), 7.91 (s, 1H), 7.59(dd, J=8.8, 1.5 Hz, 1H), 7.26 (d, J=9.4 Hz, 1H, partially covered withthe signal of solvent), 4.95 (quintet, J=7.4 Hz, 1H), 2.17 (m, 4H), 1.98(m, 2H), 1.75 (m, 2H).

Example 131N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-thiophene-2-carboxamide

Prepared as described in Example 105 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a, 39 mg, 100 μmol) and 5-methyl-2-thiophenecarboxylic acid (28 mg,200 μmol). Yield 42 mg (81%).

APCI-MS: m/z 516 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.02 (d, J=0.7 Hz, 1H), 7.75 (m, 2H),7.68 (d, J=9.2 Hz, 2H), 7.47 (d, J=3.7 Hz, 1H), 7.23-7.36 (m, 4H), 7.14(d, J=2.3 Hz, 1H), 7.08 (m, 2H), 6.84 (m, 1H), 6.73 (dd, J=3.7, 1.1 Hz,1H), 5.56 (d, J=3.9 Hz, 1H), 4.49 (m, 1H), 3.77 (s, 3H), 2.45 (s, 3H),1.32 (d, J=7.1 Hz, 3H).

Example 132N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-3-methyl-thiophene-2-carboxamide

Prepared as described in Example 105 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a, 39 mg, 100 μmol) and 3-methyl-2-thiophenecarboxylic acid (28 mg,200 μmol). Yield 43 mg (98%).

APCI-MS: m/z 516 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.7 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.2 Hz, 1H), 7.41 (d, J=5.0 Hz, 1H), 7.26-7.37 (m, 4H), 7.18(d, J=2.3 Hz, 1H), 7.08-7.14 (m, 3H), 6.88 (d, J=5.0 Hz, 1H), 6.86 (m,1H), 5.59 (d, J=4.4 Hz, 1H), 4.53 (m, 1H), 3.78 (s, 3H), 2.38 (s, 3H),1.34 (d, J=6.9 Hz, 3H).

Example 133N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1-methyl-pyrrole-2-carboxamide

Prepared as described in Example 105 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a, 39 mg, 100 mmol) and 1-methyl-2-pyrrolecarboxylic acid (25 mg, 200μmol). Yield 35 mg (70%).

APCI-MS: m/z 499 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.03 (d, J=0.7 Hz, 1H), 7.76 (m, 2H),7.69 (d, J=9.0 Hz, 1H), 7.24-7.36 (m, 4H), 7.14 (d, J=2.3 Hz, 1H), 7.09(m, 2H), 6.84 (m, 1H), 6.78 (t, J=2.0 Hz, 1H), 6.68 (dd, J=3.9, 1.6 Hz,1H), 5.95 (dd, J=3.9, 2.7 Hz, 1H), 5.53 (d, J=4.2 Hz, 1H), 4.49 (m, 1H),3.87 (s, 3H), 3.77 (s, 3H), 1.31 (d, J=6.9 Hz, 3H).

Example 134N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]thiophene-3-carboxamide

Prepared as described in Example 105 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a, 39 mg, 100 μmol) and 3-thiophenecarboxylic acid (38 mg, 300 μmol).Yield 47 mg (94%).

APCI-MS: m/z 502 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (dd, J=2.9, 1.1 Hz, 12H), 8.02 (d,J=0.7 Hz, 1H), 7.66-7.79 (m, 4H), 7.50 (dd, J=5.1, 1.2 Hz, 1H), 7.45(dd, J=5.1, 3.0 Hz, 1H), 7.24-7.36 (m, 4H), 7.14 (d, J=2.3 Hz, 1H), 7.09(m, 1H), 6.84 (m, 1H), 5.58 (d, J=4.1 Hz, 1H), 4.52 (m, 1H), 3.78 (s,3H), 1.33 (d, J=6.9 Hz, 3H).

Example 135N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]1,3-thiazole-2-carboxamide

Prepared as described in Example 1 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a, 20 mg, 50 μmol) and 1,3-thiazole-2carbonyl chloride (23 mg, 150μmol). Yield 25 mg (97%).

APCI-MS: m/z 503 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.03 (d, J=0.7 Hz, 1H), 7.98 (d, J=8.8Hz, 1H), 7.91 (d, J=3.2 Hz, 1H), 7.87 (d, J=3.2 Hz, 1H), 7.76 (m, 2H),7.69 (d, J=9.2 Hz, 1H), 7.26-7.36 (m, 4H), 7.19 (d, J=2.3 Hz, 1H), 7.10(m, 2H), 6.85 (m, 1H), 5.61 (d, J=4.4 Hz, 1H), 4.57 (m, 1H), 3.77 (s,3H), 1.40 (d, J=6.7 Hz, 3H).

Example 136N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-1,2-oxazole-3-carboxamide

Prepared as described in Example 1 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine(6a, 20 mg, 50 μmol) and 5-methylisoxazole-3-carbonyl chloride (22 mg,150 μmol). Yield 19 mg (74%).

APCI-MS: m/z 501 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.5 Hz, 1H), 7.77 (m, 2H),7.70 (d, J=9.2 Hz, 2H), 7.25-7.37 (m, 4H), 7.17 (d, J=2.1 Hz, 1H), 7.09(m, 2H), 6.85 (dd, J=8.2, 1.9 Hz, 1H), 6.41 (d, J=0.7 Hz, 1H), 5.56 (d,J=4.6 Hz, 1H), 4.56 (m, 1H), 3.78 (s, 3H), 2.44 (d, J=0.5 Hz, 3H), 1.37(d, J=6.9 Hz, 3H).

Example 137

N-[2-[1-(4-fluorophenyl)indazol-5-yl]oxy-2-phenyl-acetyl]-2-methyl-propanamide

A stirred solution of2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetamide (137b, 20mg, 60 μmol) in THF (2 ml) was cooled to 0° C., and potassium2-methylpropan-2-olate (18.6 mg, 170 μmol) was added. The mixture wasstirred at 0° C. for 10 min, and a solution of 2-methylpropanoylchloride (30 mg, 280 μmol) in THF (0.5 ml) was added. Stirring wascontinued for 30 min at 0° C. Then the sample was concentrated in vacuoand purified by semi-prep. HPLC go give white solid material, 14 mg(59%).

APCI-MS: m/z 432 [MH⁺]

¹H NMR (400 MHz, d₆-DMSO) δ 10.98 (s, 1H), 8.28 (d, J=0.7 Hz, 1H), 7.77(m, 3H), 7.60 (m, 2H), 7.47-7.36 (m, 5H), 7.26 (m, 2H), 6.24 (s, 1H),2.89 (septet, J=6.9 Hz, 1H), 1.02 (d, J=6.7 Hz, 3H), 0.96 (d, J=6.7 Hz,3H).

2-(1-(4-Fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetamide (137b)

A suspension of methyl2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (137c, 75 mg,200 μmol) in methanolic NH₃ (7 M, 1 ml) was stirred at r.t. overnight togive a clear solution. Then the solvent was removed in vacuo, and thecrude product was freeze-dried go give white solid material, 60 mg(83%).

APCI-MS: m/z 362 [MH⁺]

2-(1-(4-Fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (137c)

A mixture of 1-(4-fluorophenyl)-1H-indazol-5-ol (137d, 0.228 g, 1 mmol),methyl 2-bromo-2-phenylacetate (230 mg, 1 mmol), and cesium carbonate(652 mg, 2 mmol) in DMF (3 ml) was stirred at r.t. overnight. Then thereaction mixture was diluted with ethyl acetate (50 ml), and washed withwater (2×25 ml). The organic layer was dried over sodium sulfate, andthe solvent was removed in vacuo The residue purified by flashchromatography on silica gel (ethyl acetate/n-heptane=1:4). White solid,252 mg (67%).

APCI-MS: m/z 377 [MH⁺]

¹H NMR (400 MHz, CD₃OD) δ 8.07 (d, J=0.7 Hz, 1H), 7.68-7.57 (m, 5H),7.46-7.36 (m, 4H), 7.22 (m, 2H), 7.15 (d, J=2.1 Hz, 1H), 5.71 (s, 1H),3.77 (s, 3H).

1-(4-Fluorophenyl)-1H-indazol-5-ol (137d)

1-(4-Fluorophenyl)-5-methoxy-1H-indazole (137e, 1.0 mmol, 242 mg) wasdissolved in dichloromethane (4 ml) and BBr₃ (4 ml, 1 M indichloromethane) was added. The reaction mixture was stirred in r.t.overnight before it was quenched with water (20 ml). The product wasextracted with dichloromethane (2×20 ml) and washed with sat. NaHCO₃.The organic phase was dried over Na₂SO₄, concentrated and purified byflash chromatography on silica gel (heptane-ethyl acetate).

APCI-MS: m/z 229 [MH⁺]

¹H NMR (400 MHz, CD₃OD) δ 8.08 (s, 1H), 7.73-7.65 (m, 2H), 7.57 (d,J=9.0 Hz, 1H), 7.30 (t, J=18.7 Hz, 2H), 7.13-7.02 (m, 2H), 3.33 (s, 1H).

1-(4-Fluorophenyl)-5-methoxy-1H-indazole (137e)

A mixture of 2-fluoromethoxybenzaldehyde (2.1 mmol, 320 mg),4-fluorophenylhydrazine hydrochloride (2.1 mmol, 340 mg) and cesiumcarbonate (3 mmol, 2.0 g) in NMP (6 ml) was heated in a microwavereactor (300 W, 20 min, 150° C.). After cooling to r.t. the reactionmixture was diluted with dichloromethane (20 ml) and washed with 1M HCl,and sat. NaHCO₃. The organic layer was dried over Na₂SO₄, concentrated,and purified by flash chromatography on silica gel (heptane-ethylacetate).

APCI-MS: m/z 243 [MH⁺]

¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.76-7.67 (m, 2H), 7.61 (d,J=27.3 Hz, 1H), 7.33-7.22 (m, 2H), 7.21-7.12 (m, 2H), 3.93 (s, 3H).

Example 138(2R)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-[4-(trifluoromethyl)phenyl]propan-2-yl]-2-hydroxy-propanamide

Prepared as described in Example 105 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine(59a, 21 mg, 50 μmol) and (R)-2-hydroxypropanoic acid (12 mg, 150 μmol).Yield 14 mg (60%).

APCI-MS: m/z 502 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.05 (d, J=0.7 Hz, 1H), 7.70-7.80 (m,7H), 7.40 (br.d, J=8.7 Hz, 1H), 7.34 (m, 2H), 7.27 (dd, J=9.1, 2.4 Hz,1H), 7.19 (d, J=2.3 Hz, 1H), 5.58 (d, J=5.0 Hz, 1H), 4.41 (m, 1H), 4.05(q, J=7.1 Hz, 1H), 1.28 (d, J=6.9 Hz, 3H), 1.12 (d, J=6.7 Hz, 3H).

Example 139N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-[4-(trifluoromethyl)phenyl]propan-2-yl]-1-hydroxy-cyclopropane-1-carboxamide

Prepared as described in Example 105 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine(59a, 21 mg, 50 μmol) and 1-hydroxycyclopropanecarboxylic acid (14 mg,150 μmol). Yield 10 mg (42%).

APCI-MS: m/z 514 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.05 (8.05 (d, J=0.9 Hz, 1H), 7.81-7.70(m, 7H), 7.57 (br.d, J=8.7 Hz, 1H), 7.34 (m, 2H), 7.30 (dd, J=3.9, 9.3Hz, 2H), 7.17 (d, J=2.3 Hz, 1H), 5.61 (d, J=4.4 Hz, 1H), 4.40 (m, 1H),1.28 (d, J=6.9 Hz, 3H), 1.12 (m, 1H), 1.00 (m, 1H), 0.85 (m, 2H).

Example 140(2S)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-[4-(trifluoromethyl)phenyl]propan-2-yl]-2-hydroxy-propanamide

Prepared as described in Example 105 using(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine(59a, 21 mg, 50 μmol) and (S)-2-hydroxypropanoic acid (12 mg, 150 μmol).Yield 13 mg (56%).

APCI-MS: m/z 502 [MH⁺]

¹H NMR (400 MHz, d₆-acetone) δ 8.04 (d, J=0.9 Hz, 1H), 7.80-7.70 (m,7H), 7.42 (br.d, J=7.8 Hz, 1H), 7.34 (m, 2H), 7.28 (dd, J=9.1, 2.4 Hz,1H), 7.17 (d, J=2.1 Hz, 1H), 5.60 (d, J=4.6 Hz, 1H), 4.38 (m, 1H), 4.03(m, 1H), 1.25 (t, J=6.9 Hz, 6H).

Example 1412,2,2-trifluoro-N-((1R,2S)-1-(1-(4-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide

To a stirred suspension of(4-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)phenyl)methanol(141a, 462 mg, 1.2 mmol) in dichloromethane (50 ml) was addedtriethylamine (2.45 mL, 17.6 mmol), followed by trifluoroaceticanhydride (1.0 mL, 7.1 mmol). The suspension dissolved whenTFA-anhydride was added. The mixture was stirred at ambient temperaturefor 1.5 h. and water (1 mL) was then added. The stirring was continuedfor 30 min and the mixture was then evaporated.

Chromatography (SiO₂, 0-80% EtOAc in Heptane) afforded slightly impure2,2,2-trifluoro-N-((1R,2S)-1-(1-(4-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide(443 mg) as a beige amorphous solid.

A sample (50 mg) of the material thus obtained was subjected topreparative HPLC (Kromasil C-18, 2.5×20 cm, 50-90% acetonitrile inwater/40 min, 0.1% TfA) to afford pure2,2,2-trifluoro-N-((1R,2S)-1-(1-(4-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide(41 mg, 62%)

APCI-MS: m/z 470 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 9.52 (d, J=8.6 Hz, 1H), 8.15, d, J=0.7 Hz,1H), 7.72 (d, J=9.3 Hz, 1H), 7.66 (d, J=8.4 Hz, further coupled, 2H),7.49 (d, J=8.4 Hz, 2H), 7.43-7.39 (2H), 7.35 (t, J=7.3 Hz, furthercoupled, 2H), 7.27 (t, J=7.3 Hz, further coupled, 1H), 7.19 (dd, J=9.2and 2.3 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 5.29 (d, J=6.5 Hz, 1H), 4.56(s, 2H), 4.25 (dq, J=14.9 and 6.8 Hz, 1H), 1.33 (d, J=6.8 Hz, 3H).

(4-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)phenyl)methanol(141a)

(4-(5-iodo-1H-indazol-1-yl)phenyl)methanol (141b, 1.06 g, 3 mmol),(2R,3S-norephedrine (1.39 g, 9.2 mmol), CuI (206 mg, 1 mmol) and wasstirred under argon atmosphere in butyronitrile (14 mL) at 125° C.Caesium carbonate (5.1 g, 15.7 mmol) was added and the mixture wasvigorously stirred for 50 min, cooled, filtered and evaporated.Chromatography (SiO₂, 040% MeOH in EtOAc) afforded(4-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)phenyl)methanol(516 mg, 45%).

APCI-MS: m/z 374 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆, D₂O, added): δ 8.12 (d, J=0.6 Hz, 1H), 7.69(d, J=9.2 Hz, 1H), 7.64 (d, J=8.4 Hz, further coupled, 2H), 7.48 (d,J=8.4 Hz, 2H), 7.43-7.39 (2H), 7.38-7.31 (3H), 7.26 (t, further coupled,J=7.3 Hz, 1H), 7.21 (dd, J=9.1 and 1.8 Hz, 1H), 7.12 (d, J=1.8 Hz, 1H),5.18 (d, J=3.7 Hz, 1H), 4.55, (s, 2H), 3.23 (b, 1H), 1.08 (d, J=6.2 Hz,3H).

(4-(5-iodo-1H-indazol-1-yl)phenyl)methanol (141b)

Crude 4-(5-iodo-1H-indazol-1-yl)benzoic acid (141c, 3.05 g, 8.4 mmol)was dissolved in THF (60 mL, dried over 4 Å MS) under argon atmosphereand cooled in an ice bath. Borane-THF complex (1M, 11 mL, 11 mmol) wasadded during 5 min. The ice bath was then removed and the mixture wasallowed to reach r.t. and was finally heated at reflux for 40 min. Thereaction mixture was then cooled to r.t. and sat. aqueous NH₄Cl (25 mL)was added. After being diluted with EtOAc the reaction mixture wasextracted trice with water and finally with brine and evaporated. Theresidue was subjected to chromatography (SiO₂, 10-80% EtOAc in Heptane)to give (4-(5-iodo-1H-indazol-1-yl)phenyl)methanol (2.1 g, 71%).

APCI-MS: m/z 351 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 8.31 (m, 2H), 7.73-7.64 (4H), 7.53 (d,J=8.6 Hz, 2H), 5.31 (t, J=5.7 Hz, 1H), 4.59 (d, J=5.5 Hz, 2H).

4-(5-iodo-1H-indazol-1-yl)benzoic acid (141c)

4-(2-(2-fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (141d, 3.42 g,8.9 mmol) and potassium tert-butoxide (2.29 g, 20.5 mmol) was stirredunder argon atmosphere in NMP (45 mL) at 150° C. for 15 min. The mixturewas then cooled, diluted with water and acidified with aqueous HCl (1.7M). The precipitate that formed was collected by filtration and dried invacuo to give crude 4-(5-iodo-1H-indazol-1-yl)benzoic acid (3.05 g, 94%)

APCI-MS: m/z 365 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 13.0 (b, 1H), 8.40 (d, J=0.6 Hz, 1H), 8.33(d, J=1 Hz, further coupled, 1H), 8.14 (d, J=8.5 Hz, further coupled,2H), 7.92 (d, J=8.5 Hz, further coupled, 2H), 7.83 (d, J=8.9 Hz, furthercoupled, 1H), 7.76 (dd, J=8.9 and 1.6 Hz, 1H).

4-(2-(2-fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (141d)

4-hydrazinylbenzoic acid (1.54 g, 10 mmol), 2-fluoro-5-iodobenzaldehyde(2.52 g, 10 mmol) and caesium carbonate (3.27 g, 10 mmol) was stirred inDMF (10 mL) at r.t. for 70 min. Water (40 mL) was then added and theclear solution was acidified with aqueous HCl (1.7 M). The light yellowprecipitate that formed was collected by filtration, washed with waterand dried in vacuo to give4-(2-(2-fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (3.77 g, 98%)

APCI-MS: m/z 385 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 13-10 (b, 1H), 11.1 (s, 1H), 8.21 (dd,J=6.9 and 2.3 Hz, 1H), 8.01 (s, 1H), 7.84 (d, further coupled, J=8.8 Hz,2H), 7.67 (qd, J=8.6, 5.0 and 2.3 Hz, 1H), 7.16-7.05 (3H).

¹⁹F-NMR (300 MHz, DMSO-d₆): δ-123.3 (m).

Example 1422,2,2-trifluoro-N-((1R,2S)-1-(1-(4-(morpholinomethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide

To a stirred, ice-cooled solution of2,2,2-trifluoro-N-((1R,2S)-1-(1-(4-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide(141, 115 mg, 0.24 mmol) and triethylamine (0.35 mL, 2.5 mmol) indichloromethane (10 mL) was added methanesulfonyl chloride (38 uL, 0.49mmol). The mixture was stirred at 0° C. Additional portions ofmethanesulfonyl chloride (38 and 60 uL) were added after 35 and 60 minrespectively. After a total time of 1.5 h, the cooling bath was removed.Brine and dichloromethane (10 mL) were added and the mixture was washedwith 1M aqueous. KHSO₄ followed by sat. NaHCO₃. To the organic phase wasadded morpholine (1 mL, 11.5 mmol) and the mixture was stirredovernight.

Evaporation followed by preparative HPLC (Kromasil C-18, 2.5×20 cm,30-90% CH₃CN in water/60 min (0.1% TfA) afforded the title product as aTfA salt. This material was dissolved in MeOH and absorbed on a plug ofacidic ion exchange resin (SCX, 5 g, pre-washed with MeOH). Elution withmethanol followed by methanolic ammonia (2M) and lyophilization afforded2,2,2-trifluoro-N-((1R,2S)-1-(1-(4-(morpholinomethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide

(45 mg; 34%) as an amorphous solid.

APCI-MS: m/z 539 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 9.52 (d, J=8.5 Hz, 1H), 8.16 (d, J=0.7 Hz,1H), 7.74 (d, J=9.1 Hz, 1H), 7.66 (d, J=8.5 Hz, further coupled, 2H),7.48 (d, J=8.3 Hz, further coupled, 2H), 7.43-7.39 (2H), 7.35 (t, J=7.5Hz, further coupled, 1H), 7.27 (t, J=7.4 Hz, further coupled, 1H), 7.19(dd, J=9.2 and 2.5 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 5.29 (d, J=6.4 Hz,1H), 4.25 (dq, J=14.8 and 6.7 Hz, 1H), 3.59 (m, 4H), 3.52 (s, 2H), 2.39(m, 4H), 1.33 (d, J=6.8 Hz, 3H).

¹⁹F-NMR (300 MHz, DMSO-d₆): δ-74.3 (s).

Example 143N-((1R,2S)-1-(1-(4-((dimethylamino)methyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)-2,2,2-trifluoroacetamide

To a stirred, ice-cooled suspension of2,2,2-trifluoro-N-((1R,2S)-1-(1-(4-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide(141, 118 mg, 0.25 mmol) and triethylamine (0.35 mL, 2.5 mmol) was addedmethanesulfonyl chloride (140 μL, 1.8 mmol). After stirring for 50 minat 0° C. brine and dichloromethane (10 mL) were added. The mixture waswashed with aqueous KHSO₄ (1M) and sat. aqueous NaHCO₃. To the organicphase was added dimethylamine (0.75 mL, 11.3 mmol). The mixture wasstirred at ambient temperature for 40 min and was then evaporated.Preparative HPLC (Kromasil C-18, 2.5×20 cm, 30-90% CH₃CN in water/40 min(0.1% TfA) afforded slightly impure title compound as a TfA-salt. Thematerial was dissolved in MeOH and absorbed on a plug of acidic ionexchange resin (SCX, 5 g, pre-washed with MeOH). Eluting subsequentlywith MeOH and methanolic ammonia (2M) gave somewhat impure titlecompound. Purification by preparative HPLC on an XBridge C-18 columnusing a gradient of 50-90% acetonitrile in water containing 0.1% aqueousammonia (28%). afforded pureN-((1R,2S)-1-(1-(4-((dimethylamino)methyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)-2,2,2-trifluoroacetamide(77 mg, 61%).

APCI-MS: m/z 497 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 9.53 (d, J=8.3 Hz, 1H), 8.16 (d, J=0.6 Hz,1H), 7.74 (d, J=9.2 Hz, 1H), 7.65 (d, J=8.5 Hz, further coupled, 2H),7.45 (d, J=8.5 Hz, further coupled, 2H), 7-43-7-39(2H), 7.35 (t, J=7.5Hz, 1H), 7.27 (t, J=7.5 Hz, further coupled, 1H), 7.19 (dd, J=6.7 and2.5 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 5.29 (d, J=6.6 Hz, 1H), 4.25 (dq,J=13.5 and 7 Hz, 1H), 3.44 (s, 2H), 2.17 (s, 6H), 1.33 (d, J=6.8 Hz, 1H)

¹⁹F-NMR (300 MHz, DMSO-d₆): δ-74.3 (s)

Example 1442,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide

To a stirred suspension of(3-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)phenyl)methanol(144a, 38 mg, 0.1 mmol) in dichloromethane (4 ml) was addedtriethylamine (200 μl, 1.4 mmol) followed by trifluoroacetic anhydride(85 uL, 0.6 mmol). The mixture was stirred for 90 min and water (8drops) was then added. The mixture was evaporated and the residue wassubjected to preparative HPLC (Kromasil C-18, 2.5×20 cm) using agradient (holding 0.1% TfA) of 30-90% acetonitrile in water/30 minFractions containing the title compound was combined and lyophilized toafford2,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide(32.5 mg, 68%)

APCI-MS: m/z 470 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆, D₂O added): δ 9.60 (d, J=8.5 Hz, 1H), 8.14 (d,J=0.8 Hz, 1H), 7.72 (d, J=9.3 Hz, further coupled, 1H), 7.62 (m, 1H),7.54 (d, J=8.2 Hz, further coupled, 1H), 7.50 (d, J=7.3 Hz, 1H), 7.48(d, J=7.9 Hz, 1H), 7.42-7.22 (6H), 7.20 (dd, J=9.2 and 2.3 Hz, 1H), 7.13(d, J=2.3 Hz, 1H), 5.26 (d, J=6.9 Hz, 1H), 4.57 (s, 2H), 4.24 (m, 1H),1.33 (d, J=6.9 Hz, 3H).

(3-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)phenyl)methanol(144a)

(1R,2S)-2-amino-1-phenylpropan-1-ol (133 mg, 1.22 mmol) was dissolved inbutyronitrile (2.5 mL) under argon atmosphere in a vial. CuI (20 mg,0.17 mmol), (3-(144, 5-iodo-1H-indazol-1-yl)phenyl)methanol (92 mg, 0.26mmol) and caesium carbonate (250 mg, 1.63 mmol) was added in one portionwith stirring. The vial was closed and the mixture stirred at 125° C.for 5 h. Additional (1R,2S)-2-amino-1-phenylpropan-1-ol (90 mg, 0.6mmol), CuI (13 mg, 0.07 mmol) and caesium carbonate (280 mg, 0.86 mmol)was added in one portion with stirring at 125° C. After a total heatingtime of 5.5 h all 5-iodo-1H-indazol-1-yl)phenyl)methanol was consumed.The mixture was cooled, filtered and evaporated. The residue wassubjected to chromatography (SiO₂, 0-40% MeOH in EtOAc) to afford(3-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)phenyl)methanol(48 mg, 49%).

APCI-MS: m/z 374 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆, D₂O, added): δ 8.12 (s, 1H), 7.71 (d, J=9.1Hz, 1H), 7.63 (bs, 1H), 7.54 (d, J=8.3 Hz, further coupled, 1H), 7.50(d, J=7.3 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.43-7.19 (7H), 7.13 (d,J=2.3 Hz, 1H), 5.15 (s, 1H), 4.57, (s, 2H), 1.07 (d, J=6.0 Hz, 3H).

(3-(5-iodo-1H-indazol-1-yl)phenyl)methanol (144b)

Crude 3-(5-iodo-1H-indazol-1-yl)benzoic acid (144c, 3.5 g, 9.6 mmol) wasdissolved in THF (70 mL, dried over 4 Å MS) under argon atmosphere andcooled in an ice bath. Borane-THF complex (1M, 12 mL, 12 mmol) was addedduring 2 min. The cooling bath was removed and the mixture was stirredat r.t. for 15 min, then heated at reflux for 35 min. Additional boranereagent was added and the heating was continued for 20 min, at whichtime all starting material had been consumed. Sat. aqueous NR₄Cl (25 mL)was added followed by ethyl acetate. The phases were separated and theorganic phase was washed trice with water and finally with brine.Evaporation left a residue that was subjected to chromatography (SiO₂,10-80% EtOAc in Heptane) to afford a material that was crystallized fromethyl acetate-Heptane to give (3-(5-iodo-1H-indazol-1-yl)phenyl)methanol(1.69 g) as off white crystals. From the mother liquor was obtained inthe same way additional 223 mg of the title compound. Total yield 60%over two steps.

APCI-MS: m/z 351 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.33 (d, J=0.7 Hz, 1H), 8.31 (dd, J=1.4 and0.7 Hz, 1H), 7.73 (dd, J=8.9 and 1.6 Hz, 1H), 7.71-7.66 (2H), 7.61 (d,J=9.9 Hz, further coupled, 1H), 7.54 (t, J=7.4 Hz, 1H), 7.36 (7, J=7.4Hz, 1H), 5.37 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.7 Hz, 2H).

3-(5-iodo-1H-indazol-1-yl)benzoic acid (144c)

3-(2-(2-fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (3.47 g, 9mmol) and potassium tert. butoxide (2.3 g, 20.5 mmol) was stirred underargon atmosphere in NMP (45 mL) at 150° C. for 30 min. After cooling,the mixture was diluted with water (100 mL), acidified with aqueous HCl(1.7 M) and extracted trice with EtOAc. The combined organic phases werewashed twice with water and then with brine. Evaporation of the organicphase afforded crude title compound (3.52 g, quant.) as a light brown,amorphous, gummy solid.

APCI-MS: m/z 365 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 13.2 (b, 1H), 8.38 (s, 1H), 8.33 (s, 1H),8.24 (bs, 1H), 7.97 (d, J=8.2 Hz, further coupled, 1H), 7.81-7.68 (3H).

3-(2-(2-fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (144d)

3-hydrazinylbenzoic acid (1.52 g, 10 mmol)), 2-fluoro-5-iodobenzaldehyde(2.5 g, 10 mmol) and caesium carbonate (3.26 g, 10 mmol) were stirred inDMF (10 mL) at r.t. under argon atmosphere for 2.5 h. Water (40 mL) wasadded and the clear solution was acidified with aqueous HCl (1.7 M). Thebeige-orange precipitate that formed was collected by, filtration,washed with water and dried in vacuo to give the title compound (3.75 g,98%).

APCI-MS: m/z 385 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 12.9 (b, 1H), 8.17 (dd, J=6.9 and 2.3 Hz,1H), 7.94 (s, 1H), 7.65 (qd, J=8.7, 5.0 and 2.3 Hz, 1H), 7.63-7.60 (m,1H), 7.40-7.31 (3H), 7.09 (dd, J=10.8 and 8.7 Hz, 1H)

¹⁹F-NMR (300 MHz, DMSO-d₆, D₂O added): δ-123.4 (m)

Example 1452,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(morpholinomethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide

To a stirred, ice-cooled solution of2,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide(144, 119 mg, 0.35 mmol) and triethylamine (0.35 mL, 2.5 mmol) was addedmethanesulfonyl chloride (140 μL, 1.8 mmol). The mixture was stirred for55 min at 0° C. and brine was then added followed by dichloromethane (10mL) and aqueous KHSO₄ (1M). The phases were separated and the organicphase washed with sat aqueous NaHCO₃. To the organic phase was the addedmorpholine (1 mL, 11.5 mmol). The mixture was stirred at ambienttemperature for 16 h and was then evaporated. The residue was subjectedto preparative HPLC (Kromasil C-18, 2.5×20 cm) using a gradient (holding0.1% TfA) of 30-90% acetonitrile in water/60 min. Fractions containingthe title compound were combined and evaporated. The residue, comprisingthe TfA-salt of the title compound was dissolved in MeOH and absorbed ona plug of acidic ion exchange resin (SCX, 5 g, pre-washed with MeOH).Eluting with MeOH and methanolic ammonia (2M) subsequently affordedafter evaporation, re-dissolving in water and lyophilization2,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(morpholinomethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide(105 mg, 77%).

APCI-MS: m/z 539 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 9.52 (d, J=8.5 Hz, 1H), 8.17 (d, J=0.8H1H),7.72 (d, J=9.2 Hz, further coupled, 1H), 7.65-7-58(3H), 7.51 (d, J=7.6Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.44-7.23 (6H), 7.21 (dd, J=9.2 and 2.4Hz), 1H), 7.13 (d, J=2.4 Hz), 5.30 (d, J=6.5 Hz, 1H, 4.25 (m, 1H),3.60-3.54 (6H), 2.42-2.36 (4H), 1.34 (d, J=6.8 Hz).

¹⁹F-NMR (300 MHz, DMSO-d₆): δ-74.3 (s).

Example 146N-((1R,2S)-1-(1-(3-((dimethylamino)methyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)-2,2,2-trifluoroacetamide

To a stirred ice-cooled solution of2,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide(144, 118 mg, 0.25 mmol) and triethylamine (0.35 mL, 2.5 mmol) was addedmethanesulfonyl chloride (140 μL, 1.8 mmol). The mixture was stirred at0° C. for 65 min and brine was then added, followed by dichloromethane(10 mL).

The phases were separated and the organic phase was washed with aqueousKHSO₄ (1 M) and sat aqueous NaHCO₃ subsequently. To the organic phasewas then added dimethylamine (0.75 mL, 11.3 mmol) and the mixture wasstirred at ambient temperature for 70 min. After evaporation, theresidue was subjected to preparative HPLC (Kromasil C-18, 2.5×20 cm)using a gradient (holding 0.1% TfA) of 30-90% acetonitrile in water/40min to afford the TfA salt of the title compound. This material wasdissolved in MeOH and absorbed on a plug of acidic ion exchange resin(SCX, 5 g, pre-washed with MeOH). Eluting with MeOH and methanolicammonia (2M) subsequently gave, after lyophilization from water, aresidue that was subjected to preparative HPLC under basic conditionsusing an XBridge C-18 column and a gradient of 50-90% actonitrile inwater containing 0.1% aqueous ammonia (28%). This afforded afterlyophilizationN-((1R,2S)-1-(1-(3-((dimethylamino)methyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)-2,2,2-trifluoroacetamide(75 mg, 60%)

APCI-MS: m/z 497 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆): δ 9.53 (d, J=8.1 Hz, 1H), 8.17 (d, J=0.7 Hz,1H), 7.72 (d, J=9.2 Hz, 1H), 7.63-7.57 (2H), 7.50 (t, J=7.7 Hz, 1H)7.43-7.39 (2H), 7.37-7.32 (2H), 7.30-7.24 (2H), 7.21 (dd, J=9.2 and 2.5Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 5.29 (d, J=6.8 Hz, 1H), 4.25 (m, 1H),3.48 (s, 2H), 2.18 (s, 6H), 1.34 (d, J=6.7 Hz, 1H)

¹⁹F-NMR (300 MHz, DMSO-d₆): δ-74.3 (s)

Example 147N-(1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-yl)pivalamide

N-(1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-yl)pivalamide(147D1E1)

Racemic 147D1 (198 mg) was subjected to chiral separation on a ChiralpakfA 2×20 cm. Mobile phase: iso-Hexane-dichloromethane-methanol;500-100-5. 147D1E1 was isolated as the first eluted enantiomer: 87 mg(ee 100%).

[α]_(D)=+63° (c 0.9, MeOH)

APCI-MS: m/z 500 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.18 (d, J=0.8 Hz, 1H), 7.94 (d, J=9.5 Hz,1H), 7.81-7.67 (3H), 7.52-7.47 (2H), 7.44-7.23 (6H), 7.21 (d, J=2.1 Hz,1H), 5.86 (d, J=4.4 Hz, 1H), 5.12 (m, 1H), 1.09 (s, 9H).

¹⁹F-NMR (300 MHz, DMSO-d₆): δ-70.1 (d, J=8.5 Hz), −115.8 (m).

N-(1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-yl)pivalamide(147D1E2)

The title compound was isolated as the second eluted enantiomer from thechiral HPLC separation described for 147D1E1. Yield: 86 mg (ee 98%)[α]_(D)=−65° (c 0.9, MeOH)

APCI-MS and NMR spectral properties as for enantiomer 1

N-(1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-yl)pivalamide(147D2E1)

100 mg of racemic 147D2 were subjected to —HPLC on a chiral column asdescribed for 147D1. 147D2E1 was isolated as the first elutedenantiomer. Yield: 40 mg (ee 100%).

[α]_(D)=−82° (c 0.9, MeOH)

APCI-MS: m/z 500 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.22 (d, J=0.9 Hz, 1H), 7.95 (d, J=9.8 Hz,1H), 7.77-7.65 (3H), 7.57-7.51 (2H), 7.44-7.24 (5H), 7.18 (d, J=2.2 Hz,1H), 7.13 (dd, J=9.0 and 2.4 Hz, 1H), 5.64 (d, J=10.0 Hz, 1H), 5.00 (m,1H), 0.86 (s, 9H)

¹⁹F-NMR (300 MHz, DMSO-d₆): δ-69.16 (d, J=7.4 Hz), −115.8 (m)

N-(1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-yl)pivalamide(147D2E2)

The subtitle compound was isolated as the second eluted enantiomer fromthe chiral HPLC separation of 147D2 described for 147D2E1. Yield: 46 mg(ee 88%)

[α]_(D)=+71° (c 1, MeOH)

APCI-MS and NMR spectral properties as for enantiomer 1

N-(1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-yl)pivalamide(147D1)

1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-amine,(147aD1, 160 mg, approx. 0.39 mmol) was dissolved in dichloromethane (10mL). Pivaloyl chloride (70 uL, 0.57 mmol) was added followed bytriethylamine (80 uL, 0.57 mmol). The mixture was stirred at ambienttemperature for 100 min.

Additional pivaloyl chloride (20 uL) and triethylamine 15 uL was thenadded and the stirring was continued for 70 min. Water was added and themixture was stirred for 15 min. Dichloromethane was then added and thephases were separated. The aqueous phase was extracted once withdichloromethane and the combined organic phases were evaporated.Chromatography (SiO₂, gradient of 0-40% ethyl acetate in Heptane)afforded pure racemicN-(1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-yl)pivalamide(diastereomer 1, 170 mg, approx. 88%)

N-(1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-yl)pivalamide(147D2)

Pivaloylation and isolation of racemic1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-amine(147aD2), was performed in an analogous manner as described for 147D1.From 135 mg of amine 147aD2 was obtained 84 mg of pure racemic pivaloylester 147D2.

1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-amine(147aD1)

A solution of1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-oneoxime (147b, slightly impure, 1.08 g, 2.5 mmol) in THF (40 mL, driedover 4 A MS) was added during 10 min to a mixture of Red-Al® (2.5 mL ofa 3.5 M solution in toluene) in THF (60 mL). After the addition wascomplete the mixture was heated at reflux temperature for 1 h and wasthen cooled to r.t. Sat. aqueous ammonium chloride solution (10 mL) wasadded. The mixture was stirred for additional 10 min and was thenpartitioned between ethyl acetate and water. The turbid aqueous phasewas extracted once with ethyl acetate. The combined organic phases werewashed twice with water, once with brine and evaporated. The residue wassubjected to extensive chromatography (SiO₂, gradients of ethyl acetatein Heptane) to afford the separated diastereomeric amine products, bothhowever contaminated by unidentified side products. 160 mg of the firsteluted diastereomer (147aD1) were obtained after evaporation of thesolvents.

APCI-MS: m/z 416 [MH⁺]

1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-amine(147aD2)

521 mg of diastereomer 147aD2 were obtained as the second eluteddiastereomer from the separation on silica gel described for 147aD1

APCI-MS: m/z 416 [MH⁺]

1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-oneoxime (147b)

1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropane-2,2-diol(147c) 1.22 g, 2.8 mmol) and hydroxylamine hydrochloride (3.32 g, 48mmol) was mixed in pyridine (85 mL, dried over 4 Å MS). The mixture wasstirred at 115° C. for 30 min, after which time HPLC analysis showedcomplete reaction. Solvent was evaporated and the residue partitionedbetween ethyl acetate and water. The phases were separated and theorganic phase washed twice with water, followed by brine and thenevaporated. The residue was subjected to chromatography (SiO₂, gradientof 10-60% Ethyl acetate in Heptane) to afford somewhat impure1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-oneoxime as a 3:7 mixture of diastereomers (0.99 g, 82%).

APCI-MS: m/z 430 [MH⁺]

¹H-NMR (300 & 600 MHz, DMSO-d₆): δ 13.08 (b, 1H), 8.27 (d, J=Hz, 0.3H),8.24 (d, J=Hz, 0.7H), 7.82-7.70 (3H), 7.55-7.49 (2H), 7.48-7.24 (7H),6.49 (s, 1H)

¹⁹F-NMR (300 MHz, DMSO-d₆): δ-63.9 (s), −115.7 (m)

1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropane-2,2-diol(147c)

Methyl 2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (147d,2.5 g, 6.6 mmol) was dissolved in THF (15 mL, dried over 4 Å MS) underArgon atmosphere and cooled in an ice-bath.Trimethyl(trifluoromethyl)silane (1.18 mL, 8 mmol) was added followed byCaesium fluoride (100 mg, 0.66 mmol). The cooling bath was removed andthe stirring was continued at r.t. for 4 h. A solution oftetrabutylammonium fluoride in THF (1M, 7 mL, 7 mmol) followed by water(4 mL) was then added and the mixture was stirred for additional 1 h andthen partitioned between ethyl acetate and water. The organic phase waswashed twice with water, then brine and evaporated to afford1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropane-2,2-diol(2.74 g, 95%)

APCI-MS: m/z 433 [M⁺]

¹H-NMR (600 MHz, DMSO-d₆): δ 8.15 (d, J=0.9 Hz, 1H), 7.77-7.69 (m, 2H),7.66 (d, J=9.3 Hz, further coupled, 1H), 7.57-7.51 (2H), 7.43-7.23 (5H),7.21-7.13 (3H), 5.40 (s, 1H)

¹³C-NMR (400 MHz, DMSO-d₆): δ 160.2 (d, J=243.0 Hz), 152.4, 136.1 (d,J=2.6 Hz), 135.3, 135.0, 134.1, 129.1 (2C), 127.9, 127.5 (2C), 125.2,123.9 (d, J=8.5 Hz), 123.8 (q, J=291 Hz), 111.4, 104.2, 92.2 (q, J=28.9Hz), 80.5

¹⁹F-NMR (300 MHz, DMSO-d₆): δ-79.5 (s), −115.9 (m)

Methyl 2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (147d)

1-(4-fluorophenyl)-1H-indazol-5-ol (147e, 912 mg, 4 mmol), methyl2-bromo-2-phenylacetate (0.65 mL, 4.1 mmol) and Caesium carbonate (2.64g, 8.1 mmol) were stirred in DMF (12 mL) at ambient temp. for 55 min.and the mixture was then poured into water and extracted trice withethyl acetate. The combined organic phases were washed with water andbrine subsequently, and evaporated to afford crude methyl2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (1.59 g). Theproduct was combined with additional crude methyl2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (2.03 gobtained in the same way as above from 1.2 g of methyl2-bromo-2-phenylacetate) and crystallized from methanol to afford puremethyl 2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (2.94g) as off-white, small needles. The mother liquor was subjected tochromatography (SiO₂, gradient of 0-70% Ethyl acetate in Heptane) togive, after crystallization from methanol, additional methyl2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (272 mg).Total yield 3.2 g (92%)

APCI-MS: m/z 377 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.26 (d, J=0.9 Hz, 1H), 7.81-7.70 (3H),7.62-7.56 (2H), 7.48-7.36 (5H), 7.35 (d, J=2.4 Hz, 1H), 7.26 (dd, J=9.1and 2.4 Hz, 1H), 6.1 (s, 1H), 3.67 (s, 3H) ¹³C-NMR (400 MHz, DMSO-d₆): δ170.0, 160.3 (d, J=243.3 Hz), 152.1, 136.1 (d, J=2.6 Hz), 135.5, 135.1,134.3, 129.0, 128.7 (2C), 127.4 (2C), 125.3, 124.0 (d, J=8.6 Hz), 119.7,116.4 d, J=22.9 Hz), 111.5, 103.7, 77.8, 52.4.

¹⁹F-NMR (300 MHz, DMSO-d₆): δ-115.8 (m)

1-(4-fluorophenyl)-1H-indazol-5-ol (147e)

1-(4-fluorophenyl)-5-methoxy-1H-indazole (147f, 3.32 g, 13.7 mmol) inCH₂Cl₂ (40 mL, dried over 4 Å mol sieves). Borontribromide solution (1Min dichloromethane, 35 mL, 35 mmol) was added and the mixture wasstirred at 50° C. for 80 min. The reaction mixture was cooled to r.t.,diluted with dichloromethane and washed with ice-cold sat. aqueousNaHCO₃. Crude title compound crystallised from the organic phase at 8°C. Re-crystallization from methanol-water afforded1-(4-fluorophenyl)-1H-indazol-5-ol as light grey needles (1.88 g). Fromthe mother liquor was obtained by crystallization (methanol-water)additional title compound (0.7 g). Total yield 2.58 g (82%).

APCI-MS: m/z 229 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 9.41 (s, 1H), 8.16 (d, J=0.9 Hz. 1H),7.80-7.72 (m, 2H), 7.64 (d, J=9.1 Hz, further coupled, 1H), 7.44-7.35(m, 2H), 7.10 (dd, J=2.3 and 0.6 and Hz, 1H), 7.02 (dd, J=9.1 and 2.4Hz, 1H)

1-(4-fluorophenyl)-5-methoxy-1H-indazole (147f)

Step 1)

1-(2-fluoro-5-methoxybenzylidene)-2-(4-fluorophenyl)hydrazine

(4-fluorophenyl)hydrazine (6.5 g, 40 mmol),2-fluoro-5-methoxybenzaldehyde (6.2 g, 40 mmol) and cesium carbonate (13g, 40 mmol) were stirred in DMF (40 mL) at r.t. under argon atmospherefor 1.5 h and was then poured with stirring into water and extractedwith ethyl acetate. The organic phase was washed trice with water, thenbrine and evaporated. The residue crystallized slowly to afford thesubtitle compound as a beige-light brown crystal mass (10.21 g).

APCI-MS: m/z 263 [MH⁺]

Step 2)

1-(2-fluoro-5-methoxybenzylidene)-2-(4-fluorophenyl)hydrazine (10 g, 38mmol) and potassium tert. butoxide (5 g, 46 mmol) was stirred underargon atmosphere in NMP (50 mL) at 150° C. for 45 min. The reactionmixture was then cooled and poured with stirring into ice-water andextracted trice with ethyl acetate. The combined organic phases werewashed with water and brine, and were then evaporated. The residuecrystallized slowly from methanol-water to afford1-(4-fluorophenyl)-5-methoxy-1H-indazole as beige crystals (3.32 g, 36%)

¹H-NMR (300 MHz, DMSO-d₆): δ 8.25 (d, J=0.9 Hz, 1H), 7.81-7.74 (m, 2H),7.71 (d, J=9.2 Hz, further coupled, 1H), 7.45-7.37 (m, 2H), 7.31 (d,J=2.4 Hz, 1H), 7.13 (dd, J=9.2 and 2.5 Hz, 1H), 3.82 (s, 3H)

¹⁹F-NMR (300 MHz, DMSO-d₆): δ-115.9 (m).

Example 148 N-[(1S,2R)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyrdin-3-ylpropan-2-yl]cyclopropanecarboxamide

The racemic mixture ofN-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]cyclopropanecarboxamide(16) were separated on Thales SFC, Chiralpak IA column (75% CO₂, 25%MeOH) collecting the first eluting peak.

¹H-NMR (400 MHz, Acetone-d₆) δ 8.22 (1H, d); 8.06 (1H, s); 7.80-7.69(4H, m); 7.52 (1H, d); 7.34 (2H, dd); 7.23 (2H, dd); 7.19 (1H, d); 6.74(1H, d); 5.45 (1H, d); 4.37-4.27 (1H, m); 3.85 (3H, s); 1.54 (1H, ddd);1.27 (3H, d); 0.79-0.73 (1H, m); 0.69-0.53 (3H, m).

APCI-MS: m/z 461.1 [MH⁺].

Example 149N-[(1R,2S)-1-(3,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 486.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.51 (1H, d); 8.12 (1H, d); 7.70-7.67 (2H,m); 7.64 (1H, d); 7.37-7.33 (2H, m); 7.15 (1H, dd); 7.11 (1H, s);7.07-7.04 (3H, m); 5.18 (1H, d); 4.18-4.11 (1H, m); 2.14-2.11 (6H, m);1.26 (3H, d).

Example 150N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 494.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.50 (1H, d); 8.14 (1H, d); 7.71-7.65 (3H,m); 7.42-7.34 (4H, m); 7.23-7.14 (3H, m); 5.22 (1H, d); 4.25-4.19 (1H,m); 1.31 (3H, d).

Example 1512,2,2-trifluoro-N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 490.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.52 (1H, d); 8.13 (1H, d); 7.70-7.64 (3H,m); 7.37-7.34 (2H, m); 7.21 (1H, t); 7.16 (1H, dd); 7.11-7.07 (3H, m);5.21 (1H, d); 4.23-4.17 (1H, m); 1.29 (3H, d).

Example 1522,2,2-trifluoro-N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 476.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.53 (1H, d); 8.14 (1H, d); 7.70-7.64 (3H,m); 7.38-7.32 (3H, m); 7.22-7.12 (4H, m); 7.06 (1H, td); 5.25 (1H, d);4.26-4.18 (1H, m); 1.31 (3H, d).

Example 153N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 486.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.64 (1H, d); 8.13 (1H, d); 7.70-7.64 (3H,m); 7.37-7.33 (2H, m); 7.16 (1H, dd); 7.12 (1H, s); 7.04 (1H, d);6.96-6.93 (2H, m); 5.38 (1H, d); 4.24-4.18 (1H, m); 2.15 (3H, s); 1.26(3H, d).

Example 154N-[(1R,2S)-1-(2,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 486.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.65 (1H, d); 8.11 (1H, d); 7.70-7.63 (3H,m); 7.37-7.33 (2H, m); 7.18 (1H, d); 7.14 (1H, dd); 6.96 (1H, s); 6.94(1H, d); 6.90 (1H, d); 5.40 (1H, d); 4.24-4.19 (1H, m); 2.16 (3H, s);1.25 (3H, d).

Example 155N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 492.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.56 (1H, d); 8.13 (1H, s); 7.70-7.64 (3H,m); 7.38-7.27 (6H, m); 7.17 (1H, dd); 7.12 (1H, d); 5.22 (1H, d);4.24-4.17 (1H, m); 1.30 (3H, d).

Example 1562,2,2-trifluoro-N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 490.2 [MH+]

¹H-NMR (500 Hz, DMSO-d6): δ 9.65 (1H, d); 8.13 (1H, d); 7.70-7.64 (3H,m); 7.37-7.32 (3H, m); 7.15 (1H, dd); 7.02-6.98 (2H, m); 6.93 (1H, td);5.39 (1H, d); 4.27-4.22 (1H, m); 1.27 (2H, d).

Example 1572,2,2-trifluoro-N-[(1R,2S)-1-(5-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 490.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.68 (1H, d); 8.14 (1H, d); 7.71-7.65 (3H,m); 7.35 (2H, dd); 7.21-7.16 (2H, m); 7.07 (1H, dd); 7.01-6.94 (2H, m);5.40 (1H, d); 4.29-4.24 (1H, m); 1.28 (3H, d).

Example 1582,2,2-trifluoro-N-[(1R,2S)-1-(5-fluoro-2-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 506 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.46 (1H, d); 8.15 (1H, d); 7.71-7.65 (3H,m); 7.37-7.33 (2H, m); 7.15 (1H, dd); 7.07-6.99 (4H, m); 5.51 (1H, d);4.37-4.30 (1H, m); 3.82 (3H, s); 1.25 (3H, d).

Example 1592,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxy-3,5-dimethyl-phenyl)propan-2-yl]acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 516.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.48 (1H, d); 8.14 (1H, d); 7.71-7.64 (3H,m); 7.37-7.34 (2H, m); 7.16 (1H, dd); 7.09 (1H, d); 7.01 (2H, s); 5.13(1H, d); 4.14-4.07 (1H, m); 2.13 (6H, s); 1.26 (3H, d).

Example 160N-[(1R,2S)-1-(4-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 492.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.53 (1H, d); 8.13 (1H, d); 7.70-7.63 (3H,m); 7.40-7.33 (6H, m); 7.15 (1H, dd); 7.09 (1H, d); 5.23 (1H, d);4.23-4.18 (1H, m); 1.29 (3H, d).

Example 161N-[(1R,2S)-1-(3-chloro-5-fluoro-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 510.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.53 (1H, d); 8.16 (1H, d); 7.71-7.66 (3H,m); 7.38-7.34 (2H, m); 7.31 (1H, dt); 7.27 (1H, s); 7.20-7.16 (3H, m);5.24 (1H, d); 4.25-4.19 (1H, m); 1.31 (3H, d).

Example 1622,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2,4,5-trimethylphenyl)propan-2-yl]acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 500.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.63 (1H, d); 8.12 (1H, t); 7.70-7.63 (3H,m); 7.37-7.33 (2H, m); 7.15 (1H, dd); 7.05 (1H, s); 6.94-6.91 (2H, m);5.35 (1H, d); 4.21-4.16 (1H, m); 2.08 (3H, s); 2.05 (3H, s); 1.25 (3H,d).

Example 1632,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-tert-butylphenyl)propan-2-yl]acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 514.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.51 (1H, d); 8.13 (1H, d); 7.70-7.63 (3H,m); 7.37-7.27 (5H, m); 7.17 (1H, dd); 7.10 (1H, d); 5.26 (1H, d);4.21-4.14 (1H, m); 1.26 (3H, d); 1.18 (9H, s).

Example 1642,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2-methoxyphenyl)propan-2-yl]acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 488.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.42 (1H, d); 8.13 (1H, d); 7.70-7.64 (3H,m); 7.37-7.33 (2H, m); 7.27-7.20 (2H, m); 7.14 (1H, dd); 7.00 (1H, d);6.97 (1H, d); 6.85 (1H, t); 5.54 (1H, d); 4.36-4.30 (1H, m); 3.84 (3H,s); 1.23 (3H, d).

Example 1652,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-propylphenyl)propan-2-yl]acetamide

Prepared as described in Example 6 using corresponding starting material

APCI-MS: m/z 500.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.49 (1H, d); 8.12 (1H, d); 7.70-7.67 (2H,m); 7.64 (1H, d); 7.37-7.33 (2H, m); 7.26 (2H, d); 7.15 (1H, dd);7.12-7.08 (3H, m); 5.21 (1H, d); 4.18 (1H, dd); 1.49 (2H, sextet); 1.28(3H, d); 0.78 (3H, t).

Example 166N-[(1R,2S)-1-benzo[1,3]dioxol-5-yl-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 502.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.46 (1H, d); 8.14 (1H, d); 7.71-7.63 (3H,m); 7.37-7.34 (2H, m); 7.15 (1H, dd); 7.11 (1H, d); 6.85-6.81 (3H, m);5.92 (2H, dd); 5.14 (1H, d); 4.21-4.14 (1H, m); 1.29 (3H, d).

Example 1672,2,2-trifluoro-N-[(1R,2S)-1-(3-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 490.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.68 (1H, d); 8.13 (1H, d); 7.70-7.64 (3H,m); 7.37-7.33 (2H, m); 7.18-7.12 (3H, m); 7.05-6.99 (2H, m); 5.44 (1H,d); 4.30-4.23 (1H, m); 1.27 (3H, d).

Example 168

N-[(1R,2S)-1-(4-chloro-3-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 506.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.53 (1H, d); 8.13 (1H, d); 7.70-7.64 (3H,m); 7.37-7.32 (4H, m); 7.20 (1H, dd); 7.16 (1H, dd); 7.09 (1H, d); 5.19(1H, d); 4.21-4.14 (1H, m); 2.25 (3H, s); 1.28 (3H, d).

Example 169N-[(1R,2S)-1-(4-chloro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 506.1 [MH+]

Example 170N-[(1R,2S)-1-(4-chloro-3-fluoro-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2,2-trifluoro-acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 510.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.52 (1H, d); 8.14 (1H, d); 7.70-7.64 (3H,m); 7.53 (1H, t); 7.39-7.33 (3H, m); 7.24 (1H, s); 7.18-7.14 (2H, m);5.24 (1H, d); 4.26-4.20 (1H, m); 1.30 (3H, d).

Example 171N-[(1R,2S)-1-(3,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 474.3 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, d); 7.70-7.67 (2H, m); 7.63 (1H,d); 7.37-7.33 (2H, m); 7.30 (1H, d); 7.15 (1H, dd); 7.11 (1H, s);7.07-7.02 (3H, m); 5.18 (1H, d); 4.12-4.05 (1H, m); 2.13 (3H, s); 2.11(3H, s); 1.15 (3H, d); 0.91 (9H, s).

Example 172N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 482.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.14 (1H, d); 7.70-7.67 (2H, m); 7.65 (1H,d); 7.40-7.30 (5H, m); 7.23-7.19 (1H, m); 7.16 (1H, dd); 7.12 (1H, d);5.19 (1H, d); 4.20-4.12 (1H, m); 1.22 (3H, d); 0.88 (9H, s).

Example 173N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 478.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.70-7.67 (2H, m); 7.64 (1H,d); 7.37-7.33 (3H, m); 7.20-7.14 (2H, m); 7.10-7.05 (3H, m); 5.20 (1H,d); 4.17-4.10 (1H, m); 2.12 (3H, s); 1.19 (3H, d); 0.90 (9H, s).

Example 174N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 464.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, dd); 7.70-7.63 (3H, m); 7.38-7.30(4H, m); 7.21 (1H, d); 7.18-7.13 (2H, m); 7.10 (1H, d); 7.02 (1H, td);5.24 (1H, d); 4.20-4.13 (1H, m); 1.23-1.19 (3H, m); 0.88 (9H, s).

Example 175N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 474.3 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, d); 7.70-7.63 (3H, m); 7.37-7.33(3H, m); 7.16 (111 dd); 7.11 (1H, s); 7.01 (1H, d); 6.94-6.90 (2H, m);5.37 (1H, d); 4.18-4.11 (1H, m); 2.15 (3H, s); 1.15 (3H, d); 0.92 (9H,s).

Example 176N-[(1R,2S)-1-(2,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 474.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.11 (1H, d); 7.70-7.66 (2H, m); 7.63 (1H,d); 7.38-7.33 (3H, m); 7.18-7.13 (2H, m); 6.95-6.87 (3H, m); 5.38 (1H,d); 4.16-4.11 (1H, m); 2.16 (3H, s); 1.14 (3H, d); 0.94 (9H, s).

Example 177N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 494.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.14 (1H, d); 7.71-7.67 (2H, m); 7.64 (1H,d); 7.37-7.31 (3H, m); 7.16-7.03 (5H, m); 5.16 (1H, d); 4.16-4.10 (1H,m); 1.21-1.18 (6H, m); 0.89 (9H, s).

Example 178N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 480.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.14 (1H, t); 7.70-7.67 (2H, m); 7.65 (1H,d); 7.39-7.29 (7H, m); 7.25 (1H, dt); 7.16 (1H, dd); 7.09 (1H, d); 5.21(1H, d); 4.19-4.11 (1H, m); 1.21 (3H, d); 0.89 (9H, s).

Example 179N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 478.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, d); 7.70-7.67 (2H, m); 7.64 (1H,d); 7.41-7.31 (4H, m); 7.14 (1H, dd); 6.99-6.95 (2H, m); 6.91 (1H, td);5.37 (1H, d); 4.22-4.15 (1H, m); 1.17 (3H, d); 0.91 (9H, s).

Example 180N-[(1R,2S)-1-(5-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 478.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.70-7.64 (3H, m); 7.43 (1H,d); 7.37-7.33 (2H, m); 7.18-7.14 (2H, m); 7.05 (1H, dd); 6.98 (1H, d);6.95-6.91 (1H, m); 5.38 (1H, d); 4.23-4.16 (1H, m); 1.17 (3H, d); 0.92(9H, s).

Example 181N-[(1R,2S)-1-(5-fluoro-2-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 494.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.14 (1H, d); 7.70-7.67 (2H, m); 7.65 (1H,d); 7.37-7.33 (2H, m); 7.16-7.12 (2H, m); 7.03-6.96 (4H, m); 5.47 (1H,d); 4.37-4.30 (1H, m); 3.84 (3H, s); 1.16 (3H, d); 0.89 (9H, s).

Example 182N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxy-3,5-dimethyl-phenyl)propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 504.3 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.14 (1H, d); 7.69 (2H, dd); 7.64 (1H, d);7.35 (2H, t); 7.28 (1H, d); 7.16 (1H, dd); 7.07 (1H, d); 7.01 (2H, s);5.13 (1H, d); 4.09-4.02 (1H, m); 2.13 (6H, s); 1.16 (3H, d); 0.89 (9H,s).

Example 183N-[(1R,2S)-1-(4-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 480.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.70-7.67 (2H, m); 7.64 (1H,d); 7.40-7.32 (7H, m); 7.15 (1H, dd); 7.07 (1H, d); 5.22 (1H, d);4.19-4.12 (1H, m); 1.20 (3H, d); 0.88 (9H, s).

Example 184N-[(1R,2S)-1-(3-chloro-5-fluoro-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 498.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.16 (1H, d); 7.71-7.65 (3H, m); 7.40 (1H,d); 7.38-7.34 (2H, m); 7.27-7.24 (2H, m); 7.19-7.15 (2H, m); 7.13 (1H,d); 5.20 (1H, d); 4.18-4.12 (1H, m); 1.23 (3H, d); 0.90 (9H, s).

Example 185N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methylphenyl)propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 460.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, d); 7.70-7.62 (3H, m); 7.37-7.31(3H, m); 7.18-7.15 (4H, m); 7.05 (1H, d); 7.02-7.00 (1H, m); 5.21 (1H,d); 4.15-4.08 (1H, m); 2.23 (3H, s); 1.17 (3H, d); 0.89 (9H, s).

Example 186N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-tert-butylphenyl)propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 502.3 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.69-7.62 (3H, m); 7.37-7.33(2H, m); 7.29-7.26 (5H, m); 7.16 (1H, dd); 7.09 (1H, d); 5.22 (1H, d);4.19-4.11 (1H, m); 1.19-1.17 (12H, m); 0.85 (9H, s).

Example 187N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2-methoxyphenyl)propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 476.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, t); 7.70-7.66 (2H, m); 7.63 (1H,d); 7.37-7.33 (2H, m); 7.26 (1H, dd); 7.19 (1H, dddd); 7.14 (1H, dd);7.05 (1H, d); 7.00-6.97 (2H, m); 6.84 (1H, t); 5.50 (1H, d); 4.35-4.30(1H, m); 3.85 (3H, s); 1.13 (3H, d); 0.89 (9H, d).

Example 188N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-propylphenyl)propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 488.3 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, d); 7.69-7.66 (2H, m); 7.63 (1H,d); 7.37-7.33 (2H, m); 7.30-7.25 (3H, m); 7.15 (1H, dd); 7.09-7.06 (3H,m); 5.20 (1H, d); 4.17-4.12 (1H, m); 1.47 (2H, quintet); 1.18 (3H, d);0.87 (9H, s); 0.79 (3H, t).

Example 189N-[(1R,2S)-1-benzo[1,3]dioxol-5-yl-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 490.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.14 (1H, d); 7.70-7.67 (2H, m); 7.64 (1H,d); 7.37-7.33 (2H, m); 7.29 (1H, d); 7.14 (1H, dd); 7.09 (1H, d);6.87-6.79 (3H, m); 5.90 (2H, d); 5.14 (1H, d); 4.15-4.08 (1H, m); 1.19(3H, d); 0.90 (9H, d).

Example 190N-[(1R,2S)-1-(3-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 478.2 [MH+]

¹H NMR (499.875 MHz, DMSO-d6) δ8.12 (1H, d); 7.71-7.63 (3H, m); 7.43(1H, d); 7.38-7.32 (2H, m); 7.18-7.10 (3H, m); 7.02-6.96 (2H, m); 5.43(1H, d); 4.19 (1H, td); 1.15 (3H, t); 0.92 (9H, s);

Example 191N-[(1R,2S)-1-(4-chloro-3-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 494.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.70-7.67 (2H, m); 7.64 (1H,d); 7.37-7.29 (5H, m); 7.20 (1H, dd); 7.15 (1H, dd); 7.07 (1H, d); 5.18(1H, d); 4.16-4.08 (1H, m); 2.24 (3H, s); 1.19 (3H, d); 0.89 (9H, s).

Example 192N-[(1R,2S)-1-(3,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

5-methyl-1,3-thiazole-2-carboxylic acid (29 mg, 0.2 mmol) was dissolvedin NMP (1 mL) together with HATU (76 mg, 0.2 mmol) and DIEA (133 uL, 0.8mmol). The mixture was stirred in r.t. for 5 min before(1R,2S)-1-(3,4-dimethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine(58 mg, 0.15 mmol, prepared analogously to Example 6a with correspondingstarting material) was added. The reaction mixture was stirred in r.t.overnight before it was evaporated under reduced pressure and purifiedby semi-prep. HPLC.

APCI-MS: m/z 515.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.47 (1H, d); 8.11 (1H, d); 7.69-7.66 (2H,m); 7.63 (1H, d); 7.51 (1H, d); 7.37-7.33 (2H, m); 7.18-7.15 (2H, m);7.11-7.02 (3H, m); 5.39 (1H, d); 4.34-4.28 (1H, m); 2.10 (6H, d); 1.26(3H, d).

Example 193N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 523.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.64 (1H, d); 8.13 (1H, d); 7.70-7.64 (3H,m); 7.51 (1H, d); 7.44-7.28 (4H, m); 7.25-7.21 (1H, m); 7.18 (1H, dd);7.13 (1H, d); 5.39 (1H, d); 4.37-4.30 (1H, m); 1.33 (3H, d).

Example 194N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 519.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.60 (1H, d); 8.12 (1H, d); 7.70-7.63 (3H,m); 7.51 (1H, d); 7.37-7.33 (2H, m); 7.19-7.10 (5H, m); 5.41 (1H, d);4.37-4.30 (1H, m); 2.10 (3H, d); 1.31 (3H, d).

Example 195N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 505.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.63 (1H, d); 8.13 (1H, d); 7.70-7.64 (3H,m); 7.50 (1H, d); 7.37-7.33 (2H, m); 7.33-7.28 (1H, m); 7.24 (1H, d);7.20-7.17 (2H, m); 7.12 (1H, d); 7.03-6.99 (1H, m); 5.44 (1H, d);4.39-4.32 (1H, m); 1.32 (3H, d).

Example 196N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 515.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.53 (1H, d); 8.10 (1H, d); 7.69-7.62 (3H,m); 7.51 (1H, d); 7.51 (1H, d); 7.36-7.32 (2H, m); 7.18 (1H, dd); 7.13(1H, s); 7.03 (1H, d); 6.95-6.91 (2H, m); 5.54 (1H, d); 4.37-4.31 (1H,m); 2.13 (3H, s); 1.28 (3H, d).

Example 197N-[(1R,2S)-1-(2,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 515.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.55 (1H, d); 8.09 (1H, d); 7.69-7.61 (3H,m); 7.51 (1H, d); 7.36-7.32 (2H, m); 7.20-7.15 (2H, m); 6.96-6.93 (2H,m); 6.89 (1H, d); 5.55 (1H, d); 4.38-4.31 (1H, m); 2.15 (3H, s); 1.28(3H, d).

Example 198N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 535.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.58 (1H, d); 8.13 (1H, t); 7.70-7.63 (3H,m); 7.51 (1H, d); 7.37-7.33 (2H, m); 7.21-7.11 (4H, m); 7.04 (1H, t);5.37 (1H, d); 4.35-4.29 (1H, m); 3.71 (3H, s); 1.31 (3H, d).

Example 199N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 521.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.63 (1H, d); 8.13 (1H, d); 7.70-7.64 (3H,m); 7.50 (1H, d); 7.42 (1H, s); 7.37-7.33 (2H, m); 7.29 (1H, t);7.25-7.23 (1H, m); 7.19 (1H, dd); 7.11 (1H, d); 5.42 (1H, d); 4.37-4.30(1H, m); 1.32 (3H, d).

Example 200N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 519.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.62 (1H, d); 8.11 (1H, d); 7.69-7.62 (3H,m); 7.50 (1H, d); 7.36-7.32 (3H, m); 7.17 (1H, dd); 6.99-6.96 (2H, m);6.93-6.89 (1H, m); 5.54 (1H, d); 4.39-4.34 (1H, m); 1.30 (3H, d).

Example 201N-[(1R,2S)-1-(5-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 519.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.64 (1H, d); 8.11 (1H, d); 7.69-7.64 (3H,m); 7.51 (1H, d); 7.37-7.33 (2H, m); 7.20-7.15 (2H, m); 7.07 (1H, dd);6.99 (1H, d); 6.95-6.91 (1H, m); 5.55 (1H, d); 4.41-4.36 (1H, m); 1.31(3H, d).

Example 202N-[(1R,2S)-1-(5-fluoro-2-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 535.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.32 (1H, d); 8.14 (1H, d); 7.70-7.65 (3H,m); 7.51 (1H, d); 7.37-7.33 (2H, m); 7.19 (1H, dd); 7.07-6.96 (4H, m);5.64 (1H, d); 4.48-4.40 (1H, m); 3.81 (3H, s); 1.28 (3H, d).

Example 203N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxy-3,5-dimethyl-phenyl)propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 545.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.43 (1H, d); 8.13 (1H, d); 7.70-7.63 (3H,m); 7.51 (1H, d); 7.37-7.33 (2H, m); 7.18 (1H, dd); 7.09 (1H, d); 7.04(2H, s); 5.34 (1H, d); 4.30-4.23 (1H, m); 2.09 (6H, s); 1.26 (3H, d).

Example 204N-[(1R,2S)-1-(4-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 521.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.62 (1H, d); 8.12 (1H, d); 7.70-7.63 (3H,m); 7.50 (1H, d); 7.42-7.40 (2H, m); 7.37-7.31 (4H, m); 7.17 (1H, dd);7.09 (1H, d); 5.42 (1H, d); 4.36-4.31 (1H, m); 1.32 (3H, d).

Example 205N-[(1R,2S)-1-(3-chloro-5-fluoro-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 539.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.67 (1H, d); 8.15 (1H, d); 7.71-7.65 (3H,m); 7.51 (1H, d); 7.38-7.34 (2H, m); 7.29 (1H, s); 7.25-7.19 (2H, m);7.15 (1H, d); 5.41 (1H, d); 4.37-4.30 (1H, m); 1.34 (3H, d).

Example 206N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2,4,5-trimethylphenyl)propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 529.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.50 (1H, d); 8.10 (1H, d); 7.69-7.62 (3H,m); 7.51 (1H, d); 7.36-7.32 (2H, m); 7.17 (1H, dd); 7.06 (1H, s); 6.93(1H, d); 6.91 (1H, s); 5.51 (1H, d); 4.35-4.30 (1H, m); 2.07 (3H, s);2.04 (3H, s); 1.27 (3H, d).

Example 207N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methylphenyl)propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 501.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.50 (1H, d); 8.11 (1H, d); 7.70-7.62 (3H,m); 7.50 (1H, d); 7.37-7.33 (2H, m); 7.22-7.13 (4H, m); 7.08 (1H, d);7.01 (1H, d); 5.41 (1H, d); 4.35-4.29 (1H, m); 2.19 (3H, s); 1.28 (3H,d).

Example 208N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-tert-butylphenyl)propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 543.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.51 (1H, d); 8.11 (1H, d); 7.69-7.63 (3H,m); 7.50 (1H, d); 7.37-7.28 (6H, m); 7.19 (1H, dd); 7.10 (1H, d); 5.47(1H, d); 4.34-4.28 (1H, m); 1.27 (3H, d); 1.17 (9H, s).

Example 209N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2-methoxyphenyl)propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 517.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.25 (1H, d); 8.12 (1H, d); 7.69-7.63 (3H,m); 7.51 (1H, t); 7.37-7.33 (2H, m); 7.28 (1H, dd); 7.22-7.17 (2H, m);7.01-6.97 (2H, m); 6.85 (1H, t); 5.67 (1H, d); 4.46-4.40 (1H, m); 3.85(3H, s); 1.26 (3H, d).

Example 210N-[(1R,2S)-1-benzo[1,3]dioxol-5-yl-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 531.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.53 (1H, d); 8.13 (1H, d); 7.70-7.67 (2H,m); 7.64 (1H, d); 7.50 (1H, d); 7.37-7.33 (2H, m); 7.16 (1H, dd); 7.11(1H, d); 6.91 (1H, d); 6.87 (1H, dd); 6.78 (1H, d); 5.89 (2H, d); 5.35(1H, d); 4.35-4.28 (1H, m); 1.30 (3H, d).

Example 211N-[(1R,2S)-1-(3,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 472.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.11 (1H, s); 7.70-7.67 (2H, m); 7.64 (1H,d); 7.37-7.33 (2H, m); 7.28 (1H, d); 7.16 (1H, dd); 7.11 (2H, s);7.07-7.02 (2H, m); 5.19 (1H, d); 4.12-4.05 (1H, m); 2.13 (6H, d); 1.15(3H, d); 1.12 (3H, s); 0.75 (2H, d); 0.37 (2H, ddd)

Example 212N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 480.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.14 (1H, d); 7.70-7.67 (2H, m); 7.65 (1H,d); 7.39-7.30 (5H, m); 7.22-7.15 (2H, m); 7.10 (1H, d); 5.20 (1H, d);4.18-4.12 (1H, m); 1.22 (3H, d); 1.11 (3H, s); 0.76-0.71 (1H, m);0.65-0.60 (1H, m); 0.42-0.37 (1H, m); 0.35-0.31 (1H, m).

Example 213N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 476.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.70-7.67 (2H, m); 7.64 (1H,d); 7.37-7.33 (3H, m); 7.20-7.15 (3H, m); 7.09-7.05 (3H, m); 5.21 (1H,d); 4.16-4.10 (1H, m); 2.13 (3H, s); 1.19 (3H, d); 1.12 (3H, s);0.76-0.66 (2H, m); 0.42-0.31 (2H, m).

Example 214N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 462.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.70-7.67 (2H, m); 7.65 (1H,d); 7.40-7.30 (4H, m); 7.20 (1H, d); 7.19-7.12 (2H, m); 7.08 (1H, d);7.03 (1H, td); 5.25 (14, d); 4.20-4.12 (1H, m); 1.21 (3H, d); 1.12 (3H,d); 0.76-0.71 (1H, m); 0.68-0.64 (1H, m); 0.41-0.37 (1H, m); 0.34-0.30(1H, m).

Example 215N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 472.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, d); 7.70-7.67 (2H, m); 7.65 (1H,d); 7.37-7.32 (3H, m); 7.16 (1H, dd); 7.11 (1H, s); 7.02 (1H, d);6.94-6.90 (2H, m); 5.36 (1H, d); 4.19-4.12 (1H, m); 2.15 (3H, s); 1.16(3H, d); 1.13 (3H, s); 0.81-0.75 (2H, m); 0.42-0.33 (2H, m).

Example 216N-[(1R,2S)-1-(2,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 472.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.11 (1H, d); 7.70-7.62 (3H, m); 7.37-7.33(3H, m); 7.17-7.14 (2H, m); 6.95-6.87 (3H, m); 5.37 (1H, d); 4.18-4.12(1H, m); 2.16 (3H, s); 1.16-1.13 (6H, m); 0.82-0.77 (2H, m); 0.43-0.34(2H, m).

Example 217N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 492.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.71-7.67 (2H, m); 7.64 (1H,d); 7.37-7.31 (3H, m); 7.17-7.04 (5H, m); 5.17 (1H, d); 4.16-4.09 (1H,m); 3.74 (3H, s); 1.20 (3H, d); 1.12 (3H, s); 0.76-0.65 (2H, m);0.42-0.32 (2H, m).

Example 218N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 478.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.14 (1H, d); 7.71-7.64 (3H, m); 7.40-7.25(7H, m); 7.17 (1H, dd); 7.08 (1H, d); 5.23 (1H, d); 4.18-4.10 (1H, m);1.21 (3H, d); 1.12 (3H, s); 0.76-0.71 (1H, m); 0.68-0.63 (1H, m);0.41-0.37 (1H, m); 0.35-0.31 (1H, m).

Example 219N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 476.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, t); 7.70-7.63 (3H, m); 7.39-7.30(4H, m); 7.15 (1H, dd); 6.99-6.95 (2H, m); 6.91 (1H, td); 5.37 (1H, d);4.22-4.15 (1H, m); 1.17 (3H, d); 1.13 (3H, s); 0.80-0.73 (2H, m);0.42-0.32 (2H, m).

Example 220N-[(1R,2S)-1-(5-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 476.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.70-7.65 (3H, m); 7.41 (1H,d); 7.37-7.33 (2H, m); 7.18-7.15 (2H, m); 7.04 (1H, dd); 6.98 (1H, d);6.93 (1H, td); 5.38 (1H, d); 4.24-4.17 (1H, m); 1.18 (3H, d); 1.13 (3H,s); 0.80-0.73 (2H, m); 0.43-0.32 (2H, m).

Example 221N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxy-3,5-dimethyl-phenyl)propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 502.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.14 (1H, d); 7.71-7.67 (2H, m); 7.65 (1H,d); 7.38-7.33 (2H, m); 7.27 (1H, d); 7.17 (1H, dd); 7.05 (1H, d); 7.00(2H, s); 5.14 (1H, d); 4.09-4.02 (1H, m); 1.16 (3H, d); 1.12 (3H, s);0.76-0.68 (2H, m); 0.41-0.31 (2H, m).

Example 222N-[(1R,2S)-1-(4-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 478.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, d); 7.70-7.67 (2H, m); 7.64 (1H,d); 7.39-7.33 (7H, m); 7.16 (1H, dd); 7.06 (1H, d); 5.23 (1H, d);4.17-4.12 (1H, m); 1.20 (3H, d); 1.11 (3H, s); 0.75-0.64 (2H, m);0.41-0.30 (2H, m).

Example 223N-[(1R,2S)-1-(3-chloro-5-fluoro-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 496.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.15 (1H, d); 7.71-7.65 (3H, m); 7.42 (1H,d); 7.37-7.34 (2H, m); 7.27-7.24 (2H, m); 7.18 (1H, dd); 7.16-7.13 (1H,m); 7.12 (1H, d); 5.21 (1H, d); 4.18-4.11 (1H, m); 1.24 (3H, d); 1.13(3H, s); 0.77-0.72 (1H, m); 0.64-0.59 (1H, m); 0.42-0.32 (2H, m).

Example 224N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2,4,5-trimethylphenyl)propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 486.3 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.11 (1H, s); 7.69 (2H, dd); 7.64 (1H, d);7.38-7.29 (3H, m); 7.15 (1H, dd); 7.03 (1H, s); 6.91 (1H, d); 6.89 (1H,s); 5.33 (1H, d); 4.18-4.06 (1H, m); 2.08 (3H, s); 2.05 (3H, s);1.22-1.12 (6H, m); 0.83-0.74 (2H, m); 0.44-0.32 (2H, m);

Example 225N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methylphenyl)propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 458.2 [MH+]

¹H NMR (499.875 MHz, dmso) δ8.12 (1H, t); 7.71-7.66 (2H, m); 7.64 (1H,d); 7.38-7.29 (3H, m); 7.19-7.12 (4H, m); 7.05-7.03 (1H, m); 7.03-7.00(1H, m); 5.22 (1H, d); 4.11 (1H, dt); 2.23 (3H, s); 1.17 (3H, d); 1.12(3H, s); 0.73 (2H, t); 0.36 (2H, ddd);

Example 226N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-tert-butylphenyl)propan-2-yl]-1-methyl-cyclopropane-1carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 500.3 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.70-7.63 (3H, m); 7.37-7.33(2H, m); 7.31-7.26 (5H, m); 7.17 (1H, dd); 7.07 (1H, d); 5.24 (1H, d);4.16-4.10 (1H, m); 1.19-1.16 (12H, m); 1.10 (3H, s).

Example 227N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2-methoxyphenyl)propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 474.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, d); 7.70-7.63 (3H, m); 7.37-7.33(2H, m); 7.26 (1H, dd); 7.22-7.18 (1H, m); 7.15 (1H, dd); 7.05 (1H, d);7.01-6.98 (2H, m); 6.84 (1H, t); 5.50 (1H, d); 4.34-4.26 (1H, m); 3.85(3H, s); 1.14 (3H, d); 1.11 (3H, s); 0.76-0.71 (2H, m); 0.41-0.31 (2H,m).

Example 228N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-difluoro-propanamide

Ethyl 2,2-difluoropropanoate (200 uL) was heated neat together with(1R,2S)-1-(3,4-dimethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine(58 mg, 0.15 mmol, prepared analogously to Example 6a with correspondingstarting material) to 140° C. for 40 min. After cooling the compound waspurified by semi-prep. HPLC.

APCI-MS: m/z 490.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.75 (1H, d); 8.12 (1H, d); 7.68-7.62 (3H,m); 7.39-7.29 (4H, m); 7.22-7.12 (3H, m); 5.17 (1H, d); 4.20-4.14 (1H,m); 1.47 (3H, t); 1.28 (3H, d).

Example 2292,2-difluoro-N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]propanamide

Prepared as described in Example 228 using corresponding startingmaterial.

APCI-MS: m/z 486.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.74 (1H, d); 8.11 (1H, d); 7.67-7.61 (3H,m); 7.36-7.32 (2H, m); 7.19-7.14 (2H, m); 7.10-7.04 (3H, m); 5.17 (1H,d); 4.19-4.13 (1H, m); 2.10 (3H, s); 1.46 (3H, t); 1.26 (3H, d).

Example 2302,2-difluoro-N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]propanamide

Prepared as described in Example 228 using corresponding startingmaterial.

APCI-MS: m/z 472.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.76 (1H, d); 8.11 (1H, d); 7.68-7.62 (3H,m); 7.36-7.29 (3H, m); 7.21-7.10 (4H, m); 7.04-7.00 (1H, m); 5.21 (1H,d); 4.21-4.15 (1H, m); 1.44 (3H, t); 1.28 (3H, d).

Example 2312,2-difluoro-N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]propanamide

Prepared as described in Example 228 using corresponding startingmaterial.

APCI-MS: m/z 502.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.71 (1H, d); 8.12 (1H, d); 7.68-7.65 (2H,m); 7.63 (1H, d); 7.36-7.32 (2H, m); 7.16-7.10 (4H, m); 7.04 (1H, t);5.13 (1H, d); 4.18-4.12 (1H, m); 1.46 (3H, t); 1.27 (3H, d).

Example 232N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-difluoro-propanamide

Prepared as described in Example 228 using corresponding startingmaterial.

APCI-MS: m/z 488.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.76 (1H, d); 8.12 (1H, s); 7.68-7.63 (3H,m); 7.38-7.25 (5H, m); 7.17 (1H, dd); 7.11 (1H, d); 5.19 (1H, d);4.20-4.13 (1H, m); 1.45 (3H, t); 1.28 (3H, d).

Example 2332,2-difluoro-N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]propanamide

Prepared as described in Example 228 using corresponding startingmaterial.

APCI-MS: m/z 486.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.82 (1H, d); 8.11 (1H, s); 7.68-7.62 (3H,m); 7.36-7.31 (3H, m); 7.15-7.13 (1H, m); 6.98-6.88 (3H, m); 5.34 (1H,d); 4.24-4.19 (1H, m); 1.50 (3H, t); 1.25 (3H, d).

Example 2342,2-difluoro-N-[(1R,2S)-1-(5-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]propanamide

Prepared as described in Example 228 using corresponding startingmaterial.

APCI-MS: m/z 486.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.85 (1H, d); 8.12 (1H, s); 7.68-7.63 (3H,m); 7.36-7.32 (2H, m); 7.18-7.15 (2H, m); 7.07-7.03 (1H, m); 6.99 (1H,d); 6.95-6.91 (1H, m); 5.36 (1H, d); 4.25-4.21 (1H, m); 1.50 (3H, t);1.25 (3H, d).

Example 2352,2-difluoro-N-[(1R,2S)-1-(5-fluoro-2-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]propanamide

Prepared as described in Example 228 using corresponding startingmaterial.

APCI-MS: m/z 502.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.56 (1H, d); 8.15 (1H, d); 7.71-7.65 (3H,m); 7.37-7.33 (2H, m); 7.15 (1H, dd); 7.04-7.00 (4H, m); 5.50 (1H, d);4.35-4.30 (1H, m); 3.83 (3H, s); 1.52 (3H, t); 1.22 (3H, d).

Example 2362,2-difluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxy-3,5-dimethyl-phenyl)propan-2-yl]propanamide

Prepared as described in Example 228 using corresponding startingmaterial.

APCI-MS: m/z 512.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.65 (1H, d); 8.14 (1H, s); 7.71-7.67 (2H,m); 7.65 (1H, d); 7.38-7.33 (2H, m); 7.17-7.14 (1H, m); 7.08 (1H, d);7.01 (2H, s); 5.11 (1H, d); 4.11-4.06 (1H, m); 2.13 (6H, s); 1.46 (3H,t); 1.24 (3H, d)

Example 237N-[(1R,2S)-1-(4-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-difluoro-propanamide

Prepared as described in Example 228 using corresponding startingmaterial.

APCI-MS: m/z 488.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.72 (1H, d); 8.13 (1H, d); 7.70-7.67 (2H,m); 7.64 (1H, d); 7.39-7.33 (5H, m); 7.15 (1H, dd); 7.08 (1H, d); 5.21(1H, d); 4.20-4.13 (1H, m); 1.48 (3H, t); 1.28 (3H, d).

Example 238N-[(1R,2S)-1-(3-chloro-5-fluoro-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-difluoro-propanamide

Prepared as described in Example 228 using corresponding startingmaterial.

APCI-MS: m/z 506.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.75 (1H, d); 8.16 (1H, d); 7.71-7.65 (3H,m); 7.36 (2H, t); 7.30-7.26 (2H, m); 7.19-7.14 (3H, m); 5.20 (1H, d);4.21-4.15 (1H, m); 1.50 (2H, t); 1.30 (3H, d).

Example 2392,2-difluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methylphenyl)propan-2-yl]propanamide

Prepared as described in Example 228 using corresponding startingmaterial.

APCI-MS: m/z 468.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.69 (1H, d); 8.12 (1H, d); 7.70-7.67 (2H,m); 7.64 (1H, d); 7.37-7.33 (2H, m); 7.18-7.14 (5H, m); 7.06 (1H, d);7.02 (1H, d); 5.18 (1H, d); 4.17-4.12 (1H, m); 2.22 (3H, s); 1.46 (3H,t); 1.25 (3H, d).

Example 240N-[(1R,2S)-1-(3,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-fluoro-2-methyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 478.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.09 (1H, s); 7.90 (1H, dd); 7.66-7.63 (2H,m); 7.61 (1H, d); 7.35-7.31 (2H, m); 7.14 (1H, dd); 7.09 (1H, s);7.07-7.04 (2H, m); 7.01 (1H, d); 5.17 (1H, d); 4.16-4.09 (1H, m); 2.10(3H, s); 2.08 (3H, s); 1.30 (3H, d); 1.20 (3H, d); 1.07 (3H, d).

Example 241N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-fluoro-2-methyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 486.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.11 (1H, d); 8.07 (1H, dd); 7.67-7.61 (3H,m); 7.39-7.27 (4H, m); 7.23-7.19 (1H, m); 7.17-7.13 (2H, m); 5.17 (1H,d); 4.21-4.13 (1H, m); 1.32-1.25 (6H, m); 1.05 (3H, d).

Example 2422-fluoro-N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 482.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.10 (1H, d); 8.01 (1H, dd); 7.67-7.60 (3H,m); 7.35-7.31 (2H, m); 7.17-7.04 (5H, m); 5.18 (1H, d); 4.18-4.13 (1H,m); 2.09 (3H, s); 1.32-1.23 (6H, m); 1.05 (3H, d).

Example 2432-fluoro-N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 468.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.11 (1H, s); 8.06 (1H, dd); 7.67-7.61 (3H,m); 7.35-7.28 (3H, m); 7.22-7.11 (4H, m); 7.00 (1H, td); 5.22 (1H, d);4.21-4.15 (1H, m); 1.32-1.24 (H, m); 1.32-1.24 (6H, m); 1.03 (3H, d).

Example 244

N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-fluoro-2-methyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 478.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.09 (1H, d); 7.96 (1H, dd); 7.66-7.60 (3H,m); 7.35-7.31 (2H, m); 7.14 (1H, dd); 7.10 (1H, s); 6.99-6.96 (2H, m);6.89 (1H, d); 5.33 (1H, d); 4.23-4.17 (1H, m); 2.12 (3H, s); 1.32 (3H,d); 1.21 (3H, d); 1.08 (3H, d).

Example 245N-[(1R,2S)-1-(2,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-fluoro-2-methyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 478.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.08 (1H, d); 7.95 (1H, dd); 7.66-7.59 (3H,m); 7.34-7.30 (2H, m); 7.17-7.12 (2H, m); 6.95 (1H, d); 6.90 (1H, s);6.87 (1H, d); 5.35 (1H, d); 4.23-4.16 (1H, m); 2.12 (3H, s); 1.32 (3H,d); 1.20 (3H, d); 1.10 (3H, d).

Example 2462-fluoro-N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 498.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.10 (1H, d); 8.00 (1H, dd); 7.67-7.64 (2H,m); 7.61 (1H, d); 7.35-7.31 (2H, m); 7.16-7.11 (4H, m); 7.02 (1H, t);5.14 (1H, d); 4.18-4.12 (1H, m); 1.30 (3H, d); 1.24 (3H, d); 1.05 (3H,d).

Example 247N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-fluoro-2-methyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 484.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.11 (1H, s); 8.07 (1H, dd); 7.67-7.61 (3H,m); 7.38-7.27 (4H, m); 7.25-7.22 (1H, m); 7.16 (1H, dd); 7.11 (1H, d);5.20 (1H, d); 4.20-4.13 (1H, m); 1.32-1.25 (6H, m); 1.04 (3H, d).

Example 2482-fluoro-N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 482.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.10 (1H, d); 8.03 (1H, dd); 7.67-7.61 (3H,m); 7.35-7.31 (2H, m); 7.13 (1H, dd); 6.99 (2H, d); 6.95-6.86 (2H, m);5.33 (1H, d); 4.27-4.20 (1H, m); 1.31 (3H, d); 1.24 (3H, d); 1.07 (3H,d).

Example 2492-fluoro-N-[(1R,2S)-1-(5-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 482.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.11 (1H, d); 8.06 (1H, dd); 7.67-7.62 (3H,m); 7.35-7.31 (2H, m); 7.17-7.11 (2H, m); 7.05 (1H, dd); 7.00 (1H, d);6.90 (1H, td); 5.34 (1H, d); 4.27-4.22 (1H, m); 1.32 (3H, d); 1.24 (3H,d); 1.07 (3H, d); 1.07 (3H, d).

Example 2502-fluoro-N-[(1R,2S)-1-(5-fluoro-2-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 498.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, s); 7.74 (1H, dd); 7.68-7.62 (3H,m); 7.35-7.32 (2H, m); 7.14 (1H, dd); 7.03-6.98 (4H, m); 5.48 (1H, d);4.33-4.27 (1H, m); 1.32 (3H, d); 1.20 (3H, d); 1.08 (3H, d).

Example 251N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-3-hydroxy-2,2-dimethyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 498.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.11 (1H, s); 7.67-7.61 (3H, m); 7.50 (1H,d); 7.39-7.27 (4H, m); 7.22-7.18 (1H, m); 7.16 (1H, dd); 7.13 (1H, d);5.22 (1H, d); 4.21-4.13 (1H, m); 3.19 (2H, dd); 1.16 (3H, d); 0.84 (3H,s); 0.79 (3H, s).

Example 252N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-3-hydroxy-2,2-dimethyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 494.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.09 (1H, s); 7.67-7.60 (3H, m); 7.51 (1H,d); 7.35-7.31 (2H, m); 7.19-7.14 (2H, m); 7.10-7.04 (3H, m); 5.23 (1H,d); 4.19-4.12 (1H, m); 3.21 (2H, q); 2.10 (3H, s); 1.12 (3H, d); 0.83(6H, d).

Example 253N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-3-hydroxy-2,2-dimethyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 480.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.10 (1H, s); 7.67-7.61 (3H, m); 7.53 (1H,d); 7.35-7.29 (3H, m); 7.22-7.10 (4H, m); 7.01 (1H, td); 5.27 (1H, d);4.22-4.15 (1H, m); 3.19 (2H, dd); 1.14 (3H, d); 0.84 (3H, s); 0.79 (3H,s).

Example 254N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-3-hydroxy-2,2-dimethyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 490.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.09 (1H, d); 7.68-7.61 (3H, m); 7.56 (1H,d); 7.35-7.32 (2H, m); 7.15 (1H, dd); 7.09 (1H, s); 7.02 (1H, d); 6.95(1H, d); 6.91 (1H, d); 5.37 (1H, d); 4.18-4.12 (1H, m); 3.23 (2H, dd);2.13 (3H, s); 1.10 (3H, d); 0.85 (6H, d).

Example 255N-[(1R,2S)-1-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-3-hydroxy-2,2-dimethyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 496.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.10 (1H, d); 7.67-7.61 (3H, m); 7.52 (1H,d); 7.37-7.28 (4H, m); 7.24 (1H, dt); 7.17 (1H, dd); 7.10 (1H, d); 5.25(1H, d); 4.20-4.13 (1H, m); 3.19 (2H, dd); 1.14 (3H, d); 0.84 (3H, s);0.78 (3H, s).

Example 256N-[(1R,2S)-1-(4-fluoro-2-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-3-hydroxy-2,2-dimethyl-propanamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 494.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.09 (1H, s); 7.67-7.63 (2H, m); 7.61 (1H,d); 7.57 (1H, d); 7.35-7.29 (3H, m); 7.14 (1H, dd); 6.98-6.95 (2H, m);6.89 (1H, td); 5.38 (1H, d); 4.19-4.14 (1H, m); 3.22 (2H, dd); 1.12 (3H,d); 0.83 (6H, d).

Example 257N-[(1R,2S)-1-(3,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 462.2 [MH⁺]

¹H-NMR (500 MHz, DMSO-d6): δ 8.11 (1H, d); 7.70-7.62 (3H, m); 7.37-7.33(2H, m); 7.16 (1H, dd); 7.12 (2H, s); 7.07-7.03 (3H, m); 5.26 (1H, d);4.20-4.13 (1H, m); 3.15 (3H, d); 2.14 (3H, s); 2.12 (3H, s); 1.14 (3H,d).

Example 258N-[(1R,2S)-1-(3,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 470.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.79 (1H, d); 7.70-7.67 (2H,m); 7.65 (1H, d); 7.41-7.32 (4H, m); 7.23-7.20 (1H, m); 7.17 (1H, dd);7.12 (1H, d); 5.28 (1H, d); 4.24-4.17 (1H, m); 3.69 (2H, d); 3.15 (3H,s); 1.20 (3H, d).

Example 259N-[(1R,2S)-1-(3-fluoro-4-methyl-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 466.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, d); 7.76 (1H, d); 7.70-7.67 (2H,m); 7.64 (1H, d); 7.37-7.33 (2H, m); 7.22-7.15 (2H, m); 7.11-7.07 (3H,m); 5.29 (1H, d); 4.23-4.16 (1H, m); 3.70 (2H, d); 3.15 (3H, s); 2.12(3H, s); 1.17 (3H, d).

Example 260N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 462.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.11 (1H, d); 7.76 (1H, d); 7.70-7.64 (3H,m); 7.37-7.33 (2H, m); 7.16 (1H, dd); 7.09 (2H, s); 7.04 (1H, d);6.94-6.92 (2H, m); 5.41 (1H, d); 4.21-4.17 (1H, m); 3.74 (1H, d); 3.66(2H, d); 3.15 (3H, s); 2.14 (3H, s); 1.15 (3H, d).

Example 261N-[(1R,2S)-1-(2,4-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 462.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.10 (1H, d); 7.77 (1H, d); 7.69-7.66 (2H,m); 7.64 (1H, d); 7.37-7.33 (2H, m); 7.16-7.13 (2H, m); 6.97 (1H, s);6.92 (1H, d); 6.89 (1H, d); 5.42 (1H, d); 4.21-4.17 (1H, m); 3.76-3.66(2H, m); 3.16 (3H, s); 2.16 (3H, s); 1.14 (3H, d).

Example 262N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 482.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.73 (1H, d); 7.70-7.67 (2H,m); 7.64 (1H, d); 7.37-7.33 (2H, m); 7.18-7.05 (5H, m); 5.24 (1H, d);4.22-4.15 (1H, m); 3.74 (3H, s); 3.70 (2H, d); 3.15 (3H, s); 1.18 (3H,d).

Example 263N-[(1R,2S)-1-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2-methoxy-acetamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 452.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.13 (1H, d); 7.79 (1H, d); 7.70-7.64 (3H,m); 7.37-7.32 (2H, m); 7.22 (2H, d); 7.19-7.14 (2H, m); 7.10 (1H, d);7.04 (1H, d); 5.33 (1H, d); 4.25-4.18 (1H, m); 3.70 (1H, d); 3.14 (3H,s); 1.19 (3H, d).

Example 2642,2,2-trifluoro-N-[(1R,2S)-1-(3-fluoro-4-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]acetamide

Prepared as described in Example 6 using corresponding startingmaterial.

APCI-MS: m/z 506.1 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 9.48 (1H, d); 8.14 (1H, d); 7.70-7.63 (3H,m); 7.37-7.33 (2H, m); 7.18-7.06 (5H, m); 5.17 (1H, d); 4.22-4.16 (1H,m); 3.74 (3H, s); 1.30 (3H, d).

Example 265N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxy-2-methyl-phenyl)propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 488.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.14 (1H, d); 7.70-7.66 (2H, m); 7.62 (1H,d); 7.37-7.32 (3H, m); 7.24 (1H, d); 7.09 (1H, dd); 7.04 (1H, d);6.71-6.68 (2H, m); 5.47 (1H, d); 4.32-4.25 (1H, m); 1.18 (3H, s); 0.95(3H, d); 0.91-0.81 (2H, m); 0.47-0.40 (2H, m).

Example 266N-[(1R,2S)-1-(2,5-dimethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-2,2-difluoro-propanamide

Prepared as described in Example 228 using corresponding startingmaterial.

APCI-MS: m/z 482.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.79 (1H, d); 8.10 (1H, d); 7.68-7.62 (3H,m); 7.34 (2H, dd); 7.15 (1H, dd); 7.10 (1H, s); 7.01 (1H, d); 6.95-6.90(2H, m); 5.34 (1H, d); 4.21-4.16 (1H, m); 2.13 (3H, s); 1.49 (3H, t);1.23 (3H, d).

Example 267N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(2,4,5-trimethylphenyl)propan-2-yl]-2,2-dimethyl-propanamide

Prepared as described in Example 8 using corresponding startingmaterial.

APCI-MS: m/z 488.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.12 (1H, d); 7.70-7.67 (2H, m); 7.64 (1H,d); 7.37-7.33 (4H, m); 7.15 (1H, dd); 7.04 (1H, s); 6.91 (1H, d); 6.89(1H, s); 5.34 (1H, d); 4.13-4.09 (1H, m); 2.08 (3H, s); 2.06 (3H, s);1.14 (3H, d); 0.93 (9H, s).

Example 268N-[(1R,2S)-1-(5-fluoro-2-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-propan-2-yl]-1-methyl-cyclopropane-1-carboxamide

Prepared as described in Example 192 using corresponding startingmaterial.

APCI-MS: m/z 492.2 [MH+]

¹H-NMR (500 MHz, DMSO-d6): δ 8.14 (1H, s); 7.70-7.64 (3H, m); 7.35 (2H,dd); 7.17-7.12 (2H, m); 7.03-6.99 (4H, m); 5.47 (1H, d); 4.34-4.28 (1H,m); 3.84 (3H, s); 1.17 (3H, d); 1.11 (3H, s); 0.76-0.67 (2H, m);0.41-0.30 (2H, m).

Example 269

N-[[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]carbamoylmethyl]acetamide

(1R,2S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 200 mg, 0.51 mmol) (1) and N-acetylglycine (59.8 mg, 0.51 mmol)were dissolved in dry DMF (2 ml).O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate(213 mg, 0.56 mmol) was added followed by N,N-diisopropylethylamine (270μL, 1.53 mmol). The reaction was stirred at r.t. over night. The crudesolution was diluted by MeCN/H₂O and the product was purified onpreparative HPLC.

Yield: 250 mg (98%).

APCI-MS: m/z 491.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.17 (s, 1H), 8.02 (m, 2H), 7.77-7.67 (m,3H), 7.40 (t, J=8.5 Hz, 2H), 7.29-7.20 (m, 2H), 7.11-7.08 (m, 1H),6.97-6.91 (m, 2H), 6.83 (dd, J=8.3, 2.3 Hz, 1H), 5.32 (d, J=4.1 Hz, 1H),4.15 (m, 1H), 3.73 (s, 3H), 3.69 (dd, J=16.7, 5.9 Hz, 1H), 3.58 (dd,J=16.7, 5.6 Hz, 1H), 1.82 (s, 3H), 1.14 (d, J=7.3 Hz, 3H).

Example 2702-(carbamoylamino)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]acetamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 200 mg, 0.51 mmol) and hydantoic acid (60 mg, 0.51 mmol).

Yield: 220 mg (88%).

APCI-MS: m/z 492.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H), 8.02 (d, J=7.7 Hz, 1H),7.76-7.68 (m, 3H), 7.40 (t, J=8.6 Hz, 2H), 7.29-7.20 (m, 2H), 7.11-7.07(m, 1H), 6.97-6.93 (m, 2H), 6.83 (dd, J=7.9, 2.4 Hz, 1H), 6.11 (s, 1H),5.61 (s, 2H), 5.31 (d, J=4.4 Hz, 1H), 4.17 (m, 1H), 3.73 (s, 3H), 3.62(d, J=17.1 Hz, 1H), 3.51 (d, J=18.6 Hz, 1H), 1.13 (d, J=7.5 Hz, 3H).

Example 2713-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]imidazolidine-2,4-dione

2-(carbamoylamino)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]acetamide(270, 141 mg, 0.29 mmol) was dissolved in acetic acid (3 mL). Thereaction was heated at 120° C. with stirring for 20 h. The HOAc wasevaporated and the product was purified by preparative HPLC.

Yield: 37 mg, (27%).

APCI-MS: m/z 475.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.18 (s, 1H), 7.96 (s, 1H), 7.73 (m, 2H),7.67 (d, J=8.7 Hz, 1H), 7.39 (t, J=8.5 Hz, 2H), 7.24-7.18 (m, 3H),6.95-6.90 (m, 2H), 6.81 (dd, J=8.3, 2.6 Hz, 1H), 5.61 (d, J=11.0 Hz,1H), 4.36 (m, 1H), 3.70 (s, 3H), 3.65 (dd, J=26.0, 17.7 Hz, 2H), 1.59(t, J=3.7 Hz, 3H).

Example 2725-bromo-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]thiophene-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 70 mg, 0.18 mmol) and 5-bromothiophene-2-carboxylic acid (44.4 mg,0.21 mmol)

Yield: 90 mg, (86%).

APCI-MS: m/z 580.1/582.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.63 (d, J=6.8 Hz, 1H), 8.15 (s, 1H),7.75-7.67 (m, 3H), 7.63 (d, J=5.6 Hz, 1H), 7.39 (t, J=9.2 Hz, 2H),7.27-7.20 (m, 3H), 7.11 (s, 1H), 7.00-6.96 (m, 2H), 6.82 (dd, J=8.3, 2.4Hz, 1H), 5.38 (d, J=5.8 Hz, 1H), 4.30 (m, 1H), 3.70 (s, 3H), 1.30 (d,J=6.9 Hz, 3H).

Example 273N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methylsulfonyl-thiophene-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 70 mg, 0.18 mmol) and 5-(methylsulfonyl)thiophene-2-carboxylic acid(44.3 mg, 0.21 mmol)

Yield: 92 mg, (88%).

APCI-MS: m/z 580.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.92 (d, J=7.0 Hz, 1H), 8.16 (s, 1H), 7.86(d, J=4.9 Hz, 1H), 7.78 (d, J=4.9 Hz, 1H), 7.75-7.68 (m, 3H), 7.39 (t,J=8.7 Hz, 2H), 7.28-7.21 (m, 2H), 7.12 (d, J=2.6 Hz, 1H), 7.02-6.97 (m,2), 6.82 (dd, J=8.2, 2.4 Hz, 1H), 5.40 (d, J=5.8 Hz, 1H), 4.35 (m, 1H),3.71 (s, 3H), 3.35 (s, 3H), 1.32 (d, J=6.8 Hz, 3H).

Example 274N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 70 mg, 0.18 mmol) and 5-methylthiazole-2-carboxylic acid (30 mg,0.21 mmol).

Yield: 71 mg, (76%).

APCI-MS: m/z 517.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ8.59 (d, J=11.0 Hz, 1H), 8.17 (s, 1H),7.75-7.68 (m, 3H), 7.56 (s, 1H), 7.39 (t, J=8.7 Hz, 2H), 7.24-7.20 (m,2H), 7.13 (d, J=2.6 Hz, 1H), 7.01 (m, 2H), 6.79 (dd, J=8.2, 2.5 Hz, 1H),5.46 (d, J=6.2 Hz, 1H), 4.38 (m, 1H), 3.69 (s, 3H), 2.42 (s, 3H), 1.34(d, J=7.0 Hz, 3H).

Example 2754-cyano-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]thiophene-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 70 mg, 0.18 mmol) and 4-cyanothiophene-2-carboxylic acid (32.9 mg,0.21 mmol).

Yield: 78 mg, (82%).

APCI-MS: m/z 527.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.72 (d, J=8.3 Hz, 1H), 8.17 (s, 1H), 7.90(d, J=5.0 Hz, 1H), 7.75-7.68 (m, 3H), 7.52 (d, J=4.2 Hz, 1H), 7.39 (t,J=8.8 Hz, 2H), 7.28-7.22 (m, 2H), 7.14 (d, J=2.3 Hz, 1H), 7.04-6.99 (m,2H), 6.82 (dd, J=8.2, 2.4 Hz, 1H), 5.39 (d, J=5.6 Hz, 1H), 4.36 (m, 1H),3.72 (s, 3H), 1.33 (d, J=6.8 Hz, 3H).

Example 2765-bromo-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]furan-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 70 mg, 0.18 mmol) and 5-bromofuran-2-carboxylic acid (41.0 mg, 0.21mmol).

Yield: 92 mg, (90%).

APCI-MS: m/z 564.1/566.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.44 (d, J=8.4 Hz, 1H), 8.17 (s, 1H),7.75-7.68 (m, 3H), 7.39 (t, J=9.0 Hz, 2H), 7.26-7.20 (m, 2H), 7.12-7.10(m, 2H), 7.00-6.97 (m, 2H), 6.81 (dd, J=8.3, 2.4 Hz, 1H), 6.72 (d, J=3.5Hz, 1H), 5.37 (d, J=5.9 Hz, 1H), 4.33 (m, 1H), 3.70 (s, 3H), 1.30 (d,J=7.1 Hz, 3H).

Example 277N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-1,3,4-oxadiazole-2-carboxamide

Potassium 5-methyl-[1,3,4]oxadiazole-2-carboxylate (31.8 mg, 0.19 mmol)was mixed with acetonitrile (195 μl). A slurry was formed. The mixturewas cooled to 0-5° C. oxalyl chloride (14.99 μl, 0.17 mmol) was addedand the reaction was stirred for 1 h at 0-5° C.(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 25 mg, 0.06 mmol) was dissolved in dry THF (400 μl).N,N-diisopropylethylamine (65.6 μl, 0.38 mmol) was added. The THFsolution was cooled to 0-5° C. The acid chloride slurry was drop wiseadded to the amine solution. The reaction was stirred at 0-5° C. After1.5 h the reaction was poured into a mixture of EtOAc and dilutedammonia (ca 5%). The mixture was shaken, the organic layer collected.The water phase was washed twice with EtOAc. The combined organic layerswere dried over sodium sulphate.

The crude product was purified using prep HPLC.

Yield: 16 mg, (52%).

APCI-MS: m/z 502.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 9.27 (d, J=10.2 Hz, 1H), 8.17 (s, 1H),7.75-7.68 (m, 3H), 7.39 (t, J=8.4 Hz, 2H), 7.26-7.20 (m, 2H), 7.12 (d,J=2.4 Hz, 1H), 7.02-6.99 (m, 2H), 6.81 (dd, J=8.2, 2.5 Hz, 1H), 5.37 (d,J=7.0 Hz, 1H), 4.39 (m, 1H), 3.70 (s, 3H), 2.54 (s, 3H), 1.35 (d, J=7.7Hz, 3H).

Example 278

N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1H-imidazole-4-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 1H-imidazole-4-carboxylic acid (17 mg, 0.15mmol).

Yield: 18 mg, (29%).

APCI-MS: m/z 486.3 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.16 (s, OH), 7.75-7.68 (m, 3H), 7.39 (t,J=8.9 Hz, 2H), 7.28-7.21 (m, 2H), 7.12 (d, J=2.3 Hz, 1H), 7.01-6.98 (m,2H), 6.83 (dd, J=8.3, 2.4 Hz, 1H), 5.44 (d, J=5.2 Hz, 1H), 4.40 (m, 1H),3.71 (s, 3H), 1.28 (d, J=7.8 Hz, 3H).

Example 279N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1H-pyrazole-3-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 1H-pyrazole-3-carboxylic acid (17 mg, 0.15mmol).

Yield: 32 mg, (51.6%).

APCI-MS: m/z 486.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H), 7.75-7.67 (m, 2H), 7.39 (t,J=8.7 Hz, 1H), 7.27-7.21 (m, 1H), 7.12 (d, J=2.8 Hz, 1H), 7.02-6.99 (m,1H), 6.81 (dd, J=8.2, 2.4 Hz, 1H), 5.46 (d, J=6.3 Hz, 1H), 4.40 (m, 1H),3.70 (s, 3H), 1.28 (d, J=6.9 Hz, 3H).

Example 280N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]1,2-oxazole-3-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and isoxazole-3-carboxylic acid (17 mg, 0.15mmol).

Yield: 37 mg, (59%).

APCI-MS: m/z 487.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.78 (d, J=8.1 Hz, 1H), 8.17(s, 1H), 7.75-7.68 (m, 3H), 7.39 (t, J=9.0 Hz, 2H), 7.26-7.20 (m, 2H),7.11 (d, J=2.3 Hz, 1H), 7.02-6.99 (m, 2H), 6.82-6.79 (m, 2H), 5.38 (d,J=6.4 Hz, 1H), 4.39 (m, 1H), 3.70 (s, 3H), 1.33 (d, J=6.6 Hz, 3H).

Example 281N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1H-1,2,4-triazole-3-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 1H-1,2,4-triazole-3-carboxylic acid (17 mg,0.15 mmol).

Yield: 23 mg, (37%).

APCI-MS: m/z 487.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.17 (s, OH), 7.75-7.68 (m, 3H), 7.39 (t,J=9.0 Hz, 2H), 7.25-7.21 (m, 2H), 7.12 (d, J=3.2 Hz, 1H), 7.03-6.99 (m,2H), 6.79 (dd, J=8.4, 2.4 Hz, 1H), 5.45 (d, J=6.7 Hz, 1H), 4.42 (m, 1H),3.69 (s, 3H), 1.32 (d, J=7.2 Hz, 3H).

Example 282N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-1H-pyrazole-3-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 5-methyl-1H-pyrazole-3-carboxylic acid (19mg, 0.15 mmol).

Yield: 34 mg, (53%).

APCI-MS: m/z 500.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H), 7.87 (d, J=8.6 Hz, 1H),7.75-7.67 (m, 3H), 7.39 (t, J=9.0 Hz, 2H), 7.26-7.20 (m, 2H), 7.11 (d,J=2.0 Hz, 1H), 7.01-6.98 (m, 2H), 6.81 (dd, J=8.2, 2.3 Hz, 1H), 6.35 (s,1H), 5.45 (d, J=6.0 Hz, 1H), 4.37 (m, 1H), 3.70 (s, 3H), 2.22 (s, 3H),1.26 (d, J=7.2 Hz, 3H).

Example 283N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1-methyl-imidazole-4-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 1-methyl-1H-imidazole-4-carboxylic acid (19mg, 0.15 mmol).

Yield: 20 mg, (31%).

APCI-MS: m/z 500.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ8.16 (s, 1H), 7.81 (s, 1H), 7.75-7.68 (m,3H), 7.39 (t, J=8.8 Hz, 2H), 7.28-7.21 (m, 2H), 7.12 (d, J=2.3 Hz, 1H),7.01-6.98 (m, 2H), 6.82 (dd, J=8.2, 2.1 Hz, 1H), 5.45 (d, J=4.9 Hz, 1H),4.39 (m, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 1.26 (d, J=7.2 Hz, 3H).

Example 284N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-1,2-oxazole-4-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 5-methylisoxazole-4-carboxylic acid (19 mg,0.15 mmol).

Yield: 36 mg, (56%).

APCI-MS: m/z 501.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.31 (s, 1H), 8.19 (s, 1H), 7.76-7.68 (m,3H), 7.40 (t, J=8.7 Hz, 2H), 7.27-7.19 (m, 2H), 7.13 (d, J=2.3 Hz, 1H),7.00-6.98 (m, 2H), 6.82 (dd, J=8.2, 2.4 Hz, 1H), 5.37 (d, J=6.9 Hz, 1H),4.32 (m, 1H), 3.73 (s, 3H), 2.17 (s, 3H), 1.32 (d, J=6.5 Hz, 3H).

Example 285N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1-methyl-triazole-4-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 1-methyl-1H-1,2,3-triazole-4-carboxylic acid(19 mg, 0.15 mmol).

Yield: 44 mg, (69%).

APCI-MS: m/z 501.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.17(s, 1H), 7.75-7.68 (m, 3H), 7.39 (t, J=8.8 Hz, 2H), 7.24-7.20 (m, 2H),7.11 (d, J=2.4 Hz, 1H), 7.02-7.00 (m, 2H), 6.79 (dd, J=8.3, 2.6 Hz, 1H),5.44 (d, J=6.8 Hz, 1H), 4.41 (m, 1H), 4.05 (s, 3H), 3.69 (s, 3H), 1.32(d, J=6.7 Hz, 3H).

Example 286N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxlphenyl)propan-2-yl]-4,5-dimethyl-furan-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 4,5-dimethylfuran-2-carboxylic acid (21 mg,0.15 mmol).

Yield: 49 mg, (75%).

APCI-MS: m/z 514.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H), 8.05 (d, J=8.8 Hz, 1H),7.75-7.68 (m, 3H), 7.39 (t, J=8.9 Hz, 2H), 7.26-7.19 (m, 2H), 7.10 (d,J=2.2 Hz, 1H), 7.00-6.97 (m, 2H), 6.85 (s, 1H), 6.80 (dd, J=8.4, 2.4 Hz,1H), 5.39 (d, J=6.7 Hz, 1H), 4.31 (m, 1H), 3.70 (s, 3H), 2.21 (s, 3H),1.90 (s, 3H), 1.27 (d, J=7.6 Hz, 3H).

Example 287N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1,5-dimethyl-pyrazole-3-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid(21 mg, 0.15 mmol).

Yield: 42 mg, (64%).

APCI-MS: m/z 514.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H), 7.76-7.67 (m, 4H), 7.39 (t,J=9.4 Hz, 2H), 7.26-7.20 (m, 2H), 7.12 (d, J=2.3 Hz, 1H), 7.01-6.98 (m,2H), 6.80 (dd, J=8.3, 2.1 Hz, 1H), 6.35 (s, 1H), 5.46 (d, J=5.7 Hz, 1H),4.37 (m, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 2.23 (s, 3H), 1.25 (d, J=6.3Hz, 3H).

Example 288N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-methyl-1,3-thiazole-4-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 5-methylthiazole-4-carboxylic acid (21 mg,0.15 mmol).

Yield: 29 mg, (44%).

APCI-MS: m/z 517.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.18-8.16 (m, 1H), 7.75-7.67(m, 3H), 7.39 (t, J=8.8 Hz, 2H), 7.27-7.22 (m, 2H), 7.13 (d, J=2.3 Hz,1H), 7.02-6.99 (m, 2H), 6.82 (dd, J=8.1, 2.3 Hz, 1H), 5.50 (d, J=6.0 Hz,1H), 4.41 (m, 1H), 3.70 (s, 3H), 2.69 (s, 3H), 1.27 (d, J=6.3 Hz, 3H).

Example 289N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-4-methyl-1,3-thiazole-5-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 4-methylthiazole-5-carboxylic acid (21 mg,0.15 mmol).

Yield: 38 mg, (58%).

APCI-MS: m/z 517.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.18(s, 1H), 7.76-7.68 (m, 3H), 7.39 (t, J=9.0 Hz, 2H), 7.28-7.21 (m, 2H),7.13 (d, J=2.2 Hz, 1H), 7.03-6.98 (m, 2H), 6.83 (dd, J=8.1, 2.3 Hz, 1H),5.36 (d, J=6.7 Hz, 1H), 4.35 (m, 1H), 3.71 (s, 3H), 2.40 (s, 3H), 1.31(d, J=7.1 Hz, 3H).

Example 290N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-4-methyl-1,3-thiazole-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 4-methylthiazole-2-carboxylic acid (21 mg,0.15 mmol).

Yield: 38 mg, (58%).

APCI-MS: m/z 517.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.59 (d, J=9.7 Hz, 1H), 8.17 (s, 1H),7.75-7.68 (m, 3H), 7.57 (s, 1H), 7.39 (t, J=9.1 Hz, 2H), 7.24-7.21 (m,2H), 7.13 (d, J=2.8 Hz, 1H), 7.02-7.00 (m, 2H), 6.79 (dd, J=7.9, 2.1 Hz,1H), 5.46 (d, J=6.4 Hz, 1H), 4.38 (m, 1H), 3.69 (s, 3H), 2.42 (s, 3H),1.34 (d, J=6.6 Hz, 3H).

Example 291N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-4,5-dimethyl-thiophene-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 4,5-dimethylthiophene-2-carboxylic acid (23mg, 0.15 mmol).

Yield: 43 mg, (64%).

APCI-MS: m/z 530.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J=9.3 Hz, 1H), 8.15 (s, 1H),7.75-7.67 (m, 3H), 7.49 (s, 1H), 7.39 (t, J=8.8 Hz, 2H), 7.27-7.20 (m,2H), 7.09 (d, J=2.8 Hz, 1H), 7.01-6.96 (m, 2H), 6.81 (dd, J=8.2, 2.6 Hz,1H), 5.38 (d, J=5.8 Hz, 1H), 4.28 (m, 1H), 3.71 (s, 3H), 2.28 (s, 3H),2.07 (s, 3H), 1.27 (d, J=6.7 Hz, 3H).

Example 292N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-3-methoxy-thiophene-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 3-methoxythiophene-2-carboxylic acid (24 mg,0.15 mmol).

Yield: 44 mg, (65%).

APCI-MS: m/z 532.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.18 (s, 1H), 7.76-7.70 (m, 4H), 7.53 (d,J=9.8 Hz, 1H), 7.40 (t, J=8.6 Hz, 2H), 7.32 (t, J=8.1 Hz, 1H), 7.26 (dd,J=9.3, 2.6 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 7.09 (d, J=5.2 Hz, 1H),7.04-7.01 (m, 2H), 6.88 (dd, J=8.2, 2.3 Hz, 1H), 5.53 (d, J=4.1 Hz, 1H),4.46 (m, 1H), 3.88 (s, 3H), 3.74 (s, 3H), 1.18 (d, J=6.3 Hz, 3H).

Example 293N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1,9-diazabicyclo[4.3.0]nona-2,4,6,8-tetraene-8-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and pyrazolo[1,5-a]pyridine-2-carboxylic acid (24mg, 0.15 mmol).

Yield: 37 mg, (54%).

APCI-MS: m/z 536.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.66 (d, J=7.0 Hz, 1H), 8.26 (d, J=9.2 Hz,1H), 8.17 (s, 1H), 7.76-7.68 (m, 4H), 7.39 (t, J=8.8 Hz, 2H), 7.29-7.23(m, 3H), 7.14 (d, J=2.2 Hz, 1H), 7.04-7.00 (m, 3H), 6.94 (s, 1H), 6.80(dd, J=8.5, 2.5 Hz, 1H), 5.51 (d, J=5.9 Hz, 1H), 4.46 (m, 1H), 3.69 (s,3H), 1.33 (d, J=7.4 Hz, 3H).

Example 294N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-1H-benzoimidazole-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 1H-benzo[d]imidazole-2-carboxylic acid (24mg, 0.15 mmol).

Yield: 25 mg, (36%).

APCI-MS: m/z 536.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.80 (d, J=9.2 Hz, 1H), 8.18 (d, J=0.7 Hz,1H), 7.75-7.68 (m, 3H), 7.61 (s, 1H), 7.39 (t, J=8.8 Hz, 2H), 7.30-7.19(m, 4H), 7.14 (d, J=2.3 Hz, 1H), 7.05-7.03 (m, 2H), 6.77 (dd, J=7.3, 1.9Hz, 1H), 5.48 (d, J=6.7 Hz, 1H), 4.48 (dt, J=9.2, 6.7 Hz, 1H), 3.67 (s,3H), 1.39 (d, J=6.9 Hz, 2H)

Example 2955-chloro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]thiophene-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 5-chlorothiophene-2-carboxylic acid (24 mg,0.15 mmol).

Yield: 39 mg, (57%).

APCI-MS: m/z 536.1 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.65 (d, J=7.9 Hz, 1H), 8.16 (s, 1H),7.75-7.67 (m, 4H), 7.39 (t, J=8.8 Hz, 2H), 7.28-7.20 (m, 2H), 7.15 (d,J=4.3 Hz, 1H), 7.11 (d, J=3.0 Hz, 1H), 7.01-6.96 (m, 2H), 6.82 (dd,J=8.1, 2.4 Hz, 1H), 5.38 (d, J=5.8 Hz, 1H), 4.30 (m, 1H), 3.71 (s, 3H),1.30 (d, J=7.1 Hz, 3H).

Example 296N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]benzothiophene-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and benzo[b]thiophene-2-carboxylic acid (27 mg,0.15 mmol).

Yield: 45 mg, (64%).

APCI-MS: m/z 552.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.84 (d, J=5.0 Hz, 1H), 8.16 (s, 1H), 8.12(s, 1H), 8.00-7.91 (m, 2H), 7.74-7.68 (m, 3H), 7.46-7.36 (m, 4H),7.29-7.23 (m, 2H), 7.13 (d, J=2.2 Hz, 1H), 7.05-7.00 (m, 2H), 6.82 (dd,J=8.4, 2.8 Hz, 1H), 5.44 (d, J=5.5 Hz, 1H), 4.37 (m, 1H), 3.71 (s, 3H),1.34 (d, J=7.9 Hz, 3H).

Example 297N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]benzothiazole-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and benzo[d]thiazole-2-carboxylic acid (27 mg,0.15 mmol).

Yield: 22 mg, (31%).

APCI-MS: m/z 553.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 9.08 (d, J=9.8 Hz, 1H), 8.21-8.12 (m, 3H),7.75-7.68 (m, 3H), 7.65-7.55 (m, 2H), 7.39 (t, J=9.0 Hz, 2H), 7.26-7.20(m, 2H), 7.14 (d, J=2.1 Hz, 1H), 7.04-7.02 (m, 2H), 6.78 (dd, J=8.2, 2.5Hz, 1H), 5.48 (d, J=7.0 Hz, 1H), 4.44 (m, 1H), 3.67 (s, 3H), 1.41 (d,J=6.6 Hz, 3H).

Example 298N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-3-hydroxy-5-(trifluoromethyl)thiophene-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and3-hydroxy-5-(trifluoromethyl)thiophene-2-carboxylic acid (32 mg, 0.15mmol).

Yield: 18 mg, (24%).

APCI-MS: m/z 586.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 1H), 8.17 (s, 1H), 7.90 (d, J=9.2Hz, 1H), 7.76-7.68 (m, 3H), 7.40 (t, J=8.8 Hz, 2H), 7.31-7.18 (m, 4H),7.03-7.00 (m, 2H), 6.86 (dd, J=8.2, 2.3 Hz, 1H), 5.56 (d, J=4.8 Hz, 1H),4.46 (m, 1H), 3.74 (s, 3H), 1.20 (d, J=6.5 Hz, 3H).

Example 299N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-5-(methoxymethyl)thiophene-2-carboxamide

Prepared as described in Example 269 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and 5-(methoxymethyl)thiophene-2-carboxylic acid(26 mg, 0.15 mmol).

Yield: 48 mg, (69%).

APCI-MS: m/z 546.2 [MH⁺]

¹H-NMR (400 MHz, DMSO-d₆) δ 8.51 (d, J=7.3 Hz, 1H), 8.15 (s, 1H),7.75-7.65 (m, 4H), 7.39 (t, J=9.0 Hz, 2H), 7.28-7.21 (m, 2H), 7.11 (d,J=2.4 Hz, 1H), 7.02-6.97 (m, 3H), 6.81 (dd, J=8.1, 2.3 Hz, 1H), 5.39 (d,J=6.4 Hz, 1H), 4.54 (s, 2H), 4.31 (m, 1H), 3.71 (s, 3H), 3.26 (s, 3H),1.30 (d, J=6.9 Hz, 3H).

Example 300N-((1R,2S)-1-(2-chlorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-yl)pivalamide

Prepared as described in Example 1 using(1R,2S)-1-(2-chlorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine(300a, 18 mg, 0.05 mmol) and Pivaloyl chloride (17 μl, 0.14 mmol). Yield22 mg (100%).

APCI-MS: m/z 480.1 [MH⁺]

¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (d, J=0.8 Hz, 1H), 7.78-7.67 (m, 3H),7.55-7.48 (m, 1H), 7.46-7.24 (m, 6H), 7.19 (dd, J=9.2, 2.4 Hz, 1H), 7.03(d, J=2.3 Hz, 1H), 5.56 (d, J=6.5 Hz, 1H), 4.50-4.37 (m, 1H), 1.24 (d,J=6.9 Hz, 3H), 0.95 (s, 9H).

(1R,2S)-1-(2-chlorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine(300a)

Prepared as described in Example 6 using(1R,2S)-2-amino-1-(2-chlorophenyl)propan-1-ol hydrochloride (300b, 49mg, 0.22 mmol). Yield 21 mg (24%).

APCI-MS: m/z 396.0 [MH⁺]

¹H NMR (300 MHz, CD₃OD) δ 8.01 (d, J=0.9 Hz, 1H), 7.70-7.57 (m, 3H),7.53-7.41 (m, 2H), 7.34-7.22 (m, 5H), 6.99 (d, J=2.3 Hz, 1H), 5.66 (d,J=4.0 Hz, 1H), 3.45-3.35 (m, 1H), 1.18 (d, J=6.6 Hz, 3H).

(1R,2S)-2-amino-1-(2-chlorophenyl)propan-1-ol hydrochloride (300b)

Prepared as described in Example 6 using tert-butyl(1R,2S)-1-(2-chlorophenyl)-1-hydroxypropan-2-ylcarbamate (300c, 65 mg,0.23 mmol). Yield 49 mg (97%)

APCI-MS: m/z 186.1 [MH⁺]

tert-butyl (1R,2S)-1-(2-chlorophenyl)-1-hydroxypropan-2-ylcarbamate(300c)

Prepared as described in Example 6 using (S)-tert-butyl1-(2-chlorophenyl)-1-oxopropan-2-ylcarbamate (300d, 0.11 g, 0.39 mmol).Yield 67 mg (60%)

¹H NMR (300 MHz, CD₃OD) δ7.60 (dd, J=7.5, 1.8 Hz, 1H), 7.36-7.19 (m,3H), 5.04 (d, J=4.9 Hz, 1H), 4.02-3.91 (m, 1H), 1.38 (s, 9H), 1.03 (d,J=6.8 Hz, 3H).

(S)-tert-butyl 1-(2-chlorophenyl)-1-oxopropan-2-ylcarbamate (300d)

Prepared as described in Example 6 using (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (182 mg, 0.78 mmol)and (2-chlorophenyl)magnesium chloride (403 mg, 2.35 mmol). Yield 110 mg(50%).

¹H NMR (300 MHz, DMSO-d₆) δ 7.66-7.37 (m, 5H), 4.67 (quintet, J=7.3 Hz,1H), 1.32 (s, 9H), 1.20 (d, J=7.3 Hz, 3H).

Example 301 tert-butyl3-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-ylcarbamoyl)pyrrolidine-1-carboxylate

Prepared as described in Example 83 using(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (37 mg, 0.17 mmol).Yield 38 mg (50%).

APCI-MS: m/z 589.4 [MH⁺]

¹H NMR (300 MHz, DMSO-d₆) δ 8.18-8.11 (m, 2H), 7.79-7.66 (m, 3H), 7.40(t, J=8.8 Hz, 2H), 7.30-7.17 (m, 2H), 7.13-7.09 (m, 1H), 6.99-6.90 (m,2H), 6.82 (dd, J=8.2, 2.4 Hz, 1H), 5.27 (d, J=4.9 Hz, 1H), 4.23-4.10 (m,1H), 3.72 (s, 3H), 3.33-2.79 (m, 5H), 1.97-1.49 (m, 2H), 1.37 (s, 9H),1.17 (d, J=6.8 Hz, 3H).

Example 3022,2-difluoro-N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)propanamide

Ethyl 2,2-difluoropropanoate (400 μl) and(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 135 mg, 0.34 mmol) was heated to 150° C. for 30 min. Then it wasdiluted with acetonitrile and purified by semiprep HPLC followed byflash chromatography on silica gel (n-heptane/ethyl acetate, 4:1) Yield60 mg (36%).

APCI-MS: m/z 484.2 [MH⁺]

¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (d, J=8.7 Hz, 1H), 8.18 (d, J=0.8 Hz,1H), 7.78-7.65 (m, 3H), 7.44-7.35 (m, 2H), 7.29-7.16 (m, 2H), 7.11 (d,J=2.1 Hz, 1H), 7.00-6.93 (m, 2H), 6.82 (dd, J=8.0, 2.3 Hz, 1H), 5.24 (d,J=7.0 Hz, 1H), 4.28-4.14 (m, 1H), 3.72 (s, 3H), 1.52 (t, J=19.5 Hz, 3H),1.31 (d, J=6.6 Hz, 3H).

Example 303(R)-2-amino-N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)propanamidetrifluoroacetic acid salt

Tert-butyl(R)-1-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-ylamino)-1-oxopropan-2-ylcarbamate(303a, 25 mg, 0.04 mmol) in DCM/TFA 1:1 (1 ml) was shaken for 1 h andthen evaporated. Yield 25 mg (100%).

APCI-MS: m/z 463.1 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (d, J=8.0 Hz, 1H), 8.17 (d, J=0.7 Hz,1H), 8.02 (d, J=4.1 Hz, 3H), 7.78-7.68 (m, 3H), 7.44-7.37 (m, 2H), 7.30(t, J=7.9 Hz, 1H), 7.23 (dd, J=9.1, 2.4 Hz, 1H), 7.07 (d, J=2.1 Hz, 1H),6.98-6.84 (m, 3H), 5.37 (d, J=3.5 Hz, 1H), 4.20-4.11 (m, 1H), 3.81-3.71(m, 4H), 1.33 (d, J=7.1 Hz, 3H), 1.18 (d, J=6.7 Hz, 3H).

tert-butyl(R)-1-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-ylamino)-1-oxopropan-2-ylcarbamate(303a)

Prepared as described in Example 83 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and (R)-2-(tert-butoxycarbonylamino)propanoicacid (32 mg, 0.17 mmol). Yield 25 mg (34%).

APCI-MS: m/z 563.4 [MH⁺]

Example 304(R)-N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)pyrrolidine-2-carboxamidetrifluoroacetic acid salt

Prepared as described in Example 303 from (R)-tert-butyl2-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-ylcarbamoyl)pyrrolidine-1-carboxylate(304a, 31 mg, 0.05 mmol) Yield 32 mg (100%).

APCI-MS: m/z 489.1 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.76 (d, J=8.1 Hz, 1H), 8.55(s, 1H), 8.17 (d, J=0.7 Hz, 1H), 7.77-7.69 (m, 3H), 7.41 (t, J=8.8 Hz,2H), 7.30 (t, J=8.0 Hz, 1H), 7.23 (dd, J=9.2, 2.3 Hz, 1H), 7.09 (d,J=2.3 Hz, 1H), 6.98-6.91 (m, 2H), 6.86 (dd, J=8.1, 2.1 Hz, 1H), 5.38 (d,J=4.1 Hz, 1H), 4.24-4.14 (m, 1H), 4.11-4.02 (m, 1H), 3.73 (s, 3H),3.31-3.13 (m, 2H), 2.35-2.22 (m, 1H), 1.93-1.74 (m, 3H), 1.20 (d, J=6.7Hz, 3H).

(R)-tert-butyl2-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-ylcarbamoyl)pyrrolidine-1-carboxylate(304a)

Prepared as described in Example 83 from(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine(6a, 50 mg, 0.13 mmol) and(R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (37 mg, 0.17mmol). Yield 31 mg (41%).

APCI-MS: m/z 589.5 [MH⁺]

Example 305N-((2S,3S)-4-(2,4-difluorophenoxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)butan-2-yl)-2,2,2-trifluoroacetamide

Prepared as described in Example 1 using(2S,3S)-4-(2,4-difluorophenoxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)butan-2-amine(90 mg, 0.21 mmol) and 2,2,2-trifluoroacetic anhydride (0.119 mL, 0.84mmol). Yield 71 mg (64%)

APCI-MS: m/z 534.3 [MH⁺]

¹H-NMR (400 MHz, CD₃OD): δ 8.13 (d, J=0.7 Hz, 1H), 7.71 (m, 2H), 7.64(d, J=9.0 Hz, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.32 (m, 2H), 7.25 (dd,J₁=2.3 Hz, J₂=9.1 Hz, 1H), 7.09 (m, 1H), 6.97 (m, 1H), 6.85 (m, 1H),4.79 (m, 1H), 4.51 (p, J=6.5 Hz, 1H), 4.34 (dd, J₁=10.6 Hz, J₂=3.9 Hz,1H), 4.26 (dd, J₁=10.6 Hz, J₂=5.4 Hz, 1H), 1.42 (d, J=7.1 Hz, 3H).

(2S,3S)-4-(2,4-difluorophenoxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)butan-2-amine(305a)

Prepared as described in Example 1a from(2S,3S)-4-(2,4-difluorophenoxy)-3-hydroxybutan-2-ammonium chloride (290mg, 1.14 mmol) and 1-(4-fluorophenyl)-5-iodo-1H-indazole (464 mg, 1.37mmol). Yield: 90 mg (18%).

¹H-NMR (400 MHz, CD₂Cl₂): δ 8.07 (s, 1H), 7.68 (m, 2H), 7.60 (d, J=9.0Hz, 1H), 7.37 (broad s, 1H), 7.28-7.18 (m, 3H), 6.97 (m, 1H), 6.87 (m,1H), 6.79 (m, 1H), 4.45 (broad s, 1H), 4.33 (m, 2H), 3.48 (broad s, 1H),1.27 (d, J=6.0 Hz, 3H).

(2S,3S)-4-(2,4-difluorophenoxy)-3-hydroxybutan-2-ammonium chloride(305b)

Benzyl (2S,3S)-4-(2,4-difluorophenoxy)-3-hydroxybutan-2-ylcarbamate (426mg, 1.21 mmol) in ethanol (20 mL) was hydrogenated over Pd (10% oncarbon) (40.0 mg) at r.t. and atmospheric pressure overnight. Themixture was filtered through celite, evaporated, dissolved in ethanoland filtered through a syringe filter. On evaporation a white solid wasobtained. This was dissolved in ethanol (4 mL) and diethyl ether (6 mL)and 1M HCl in diethyl ether was added (1.5 mL) under stirring.Evaporation, coevaporation from dichloromethane/diethylether gave thetitle compound as a solid, (290 mg, 94%).

¹H-NMR (400 MHz, CD₃OD): δ 7.16 (m, 1H), 7.01 (m, 1H), 6.90 (m, 1H),4.18-4.01 (m, 3H), 3.58 (m, 1H), 1.32 (d, J=6.9 Hz, 3H).

Benzyl (2S,3S)-4-(2,4-difluorophenoxy)-3-hydroxybutan-2-ylcarbamate(305c)

Prepared as described in Example 6c from (S)-benzyl4-(2,4-difluorophenoxy)-3-oxobutan-2-ylcarbamate (657 mg, 1.88 mmol).Yield: 426 mg (64% yield)

¹H-NMR (400 MHz, CD₂Cl₂): δ 7.39-7.28 (m, 5H), 7.00-6.78 (m, 3H), 5.18(broad s, 1H), 5.09 (s, 2H), 4.11-3.88 (m, 4H), 1.22 (d, J=6.9 Hz, 3H).

(S)-benzyl 4-(2,4-difluorophenoxy)-3-oxobutan-2-ylcarbamate (305d)

A mixture of (S)-benzyl 4-bromo-3-oxobutan-2-ylcarbamate (preparedaccording to R. V. Hoffman et al., J. Org. Chem. 2001, 66, 5790-5795)(600 mg, 2.00 mmol), 2,4-difluorophenol (312 mg, 2.40 mmol) andpotassium fluoride (380 mg, 6.54 mmol) in DMF (4 mL) was stirred at r.t.for 17 h. Water (15 mL) and dichloromethane (3 mL) were added and themixture was stirred for 30 min. The mixture was added to a phaseseparator. The water phase was once more stirred with dichloromethane (3mL), and added to the phase separator. The organic phases wereconcentrated and the residue was purified by flash chromatography onsilica gel (cyclohexane/ethyl acetate 3/1) to give the title compound asa white solid (658 mg, 94% yield).

¹H-NMR (400 MHz, CD₂Cl₂): δ 7.40-7.28 (m, 5H), 6.95-6.86 (m, 2H), 6.81(m, 1H), 5.40 (broad s, 1H), 5.10 (s 2H), 4.81 (m, 2H), 4.60 (p, J=7.1Hz, 1H), 1.41 (d, J=7.2 Hz, 3H).

Example 306N-((1R,2S)-1-(2,3-dihydrobenzofuran-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-yl)-2,2-difluoropropanamide

To a solution of(1R,2S)-1-(2,3-dihydrobenzofuran-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine(306a, 85 mg, 0.21 mmol) in NMP (1 mL) was added a solution of2,2-difluoropropanoic acid (37 mg, 0.34 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (0.128 g, 340 nmol), andN-ethyl-N-isopropylpropan-2-amine (140 μL, 840 μmol) in NMP (2 mL). Themixture was stirred at r.t. for 2 h. Then aq. HCl (1N, 30 mL) was added,and the mixture was extracted with ethyl acetate (3×45 ml). The organicphase was dried and purified by flash chromatography on silica gel withethyl acetane/n-heptane (2:1) to give 65 mg (62%) of the title compound.

APCI-MS: m/z 496.3 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) ∂ 8.67 (d, J=8.1 Hz, 1H), 8.18 (d, J=0.7 Hz,1H), 7.74 (dd, J=9.0, 4.8 Hz, 2H), 7.69 (d, J=9.2 Hz, 1H), 7.40 (t,J=8.8 Hz, 2H), 7.18 (m, 2H), 7.09 (d, J=2.3 Hz, 1H), 6.86 (d, J=7.6 Hz,1H), 6.76 (s, 1H), 5.21 (d, J=6.7 Hz, 1H), 4.47 (dd, J=15.1, 8.9 Hz,2H), 4.17 (m1H), 3.11 (t, J=8.7 Hz, 2H), 1.63-1.47 (m, 3H), 1.29 (d,J=6.7 Hz, 3H).

(1R,2S)-1-(2,3-Dihydrobenzofuran-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine(306a)

A stirred mixture of(1R,2R)-2-amino-1-(2,3-dihydrobenzofuran-6-yl)propan-1-ol (306b, 180 mg,0.93 mmol), 1-(4-fluorophenyl)-5-iodo-1H-indazole (346 mg, 1.02 mmol),and cesium carbonate (0.910 g, 2.79 mmol) in butyronitrile (2 mL) wasdegassed for 5 min. Then copper(I) iodide (35 mg, 190 μmol) was added.The tube was sealed and heated at 105° C. for 12 h. The solvent wasremoved, the residue was taken in dichloromethane (20 mL), and filteredon a prepact silica column (10 g), washed with dichloromethane (50 ml)followed by ethyl acetate (50 ml). Than the product was eluted with amixture of 0.35M ammonia solution in ethylacetate/methanol (5:95) (100ml) to give 80 mg (22%) of subtitle compound.

APCI-MS: m/z 404 [MH⁺]

(1R,2R)-2-Amino-1-(2,3-dihydrobenzofuran-6-yl)propan-1-ol (306b)

t-Butyl(1R,2R)-1-(2,3-dihydrobenzofuran-6-yl)-1-hydroxypropan-2-ylcarbamate(1.58 g, 5.39 mmol) was stirred in a solution of HCl in EtOAc (1M, 20ml) at 60° C. for 2 h. After cooling the solid precipitate was filteredand dried to afford the subtitle compound as hydrochloride (1.22 g,98%).

APCI-MS: m/z 194 [MH⁺]

¹H NMR (400 MHz, dmso) ∂ 7.98 (s, 3H), 7.20 (d, J=7.6 Hz, 1H), 6.80 (d,J=7.6 Hz, 1H), 6.75 (s, 1H), 5.97 (d, J=4.2 Hz, 1H), 4.83 (t, J=3.5 Hz,2H), 4.52 (t, J=8.7 Hz, 1H), 3.36 (m, 1H), 3.15 (t, J=8.7 Hz, 2H), 0.93(d, J=6.7 Hz, 3H).

t-Butyl(1R,2R)-1-(2,3-dihydrobenzofuran-6-yl)-1-hydroxypropan-2-ylcarbamate(306c)

(R)-t-butyl 1-(2,3-dihydrobenzofuran-6-yl)-1-oxopropan-2-ylcarbamate(306d, 2.21 g, 7.59 mmol) was dissolved in propan-2-ol (6.35 mL, 83.4mmol) and toluene (10 mL). Al(OiPr)₃ (0.310 g, 1.52 mmol) was added, andthe reaction vessel was capped and flushed with argon. The mixture wasstirred at 50° C. overnight. Then another portion of Al(OiPr)₃ (330 mg)was added, and stirring was continued for 5 h. The mixture was cooled tor.t., and partitioned between aq. HCl (1N, 25 ml) and ethyl acetate (80ml). The organic layer was separated and dried. The solvent was removedin vacuo and purified by flash chromatography on silica gel withn-heptane/ethyl acetate (6:4) to give 1.58 g (71%) of subtitle compound.

APCI-MS: m/z 194.2 [MH⁺-BOC]

(R)-t-Butyl 1-(2,3-dihydrobenzofuran-6-yl)-1-oxopropan-2-ylcarbamate(306d)

Magnesium (711 mg, 29.3 mmol) was placed in a screw-cap reaction tube,and a solution of 6-bromo-2,3-dihydrobenzofuran (4.16 g, 20.9 mmol) intetrahydrofuran (30 mL) was added, followed by a small crystal ofiodine. The tube was sealed and flushed with argon. The mixture washeated at 60° C. for 1 h, and then the reaction mixture was allowed tocool to r.t. A slurry of (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (4.85 g, 20.9 mmol)in THF (20 ml) was cooled on a acetone/ice bath to −10° C., and asolution isopropylmagnesium chloride (2 M in THF, 10.5 mL, 21 mmol) wasslowly added. The mixture was stirred for 15 min, the cooling bath wasremoved. Stirring was continued for 10 min. Then the preformed Grignardreagent was added in small portions with stirring. After the additionthe mixture was allowed to reach r.t. and stirred for 2 h. The solventwas evaporated, and the mixture was poured into an ice-cold ethylacetate (150 ml) and aq. HCl (1M, 35 ml) mixture. The organic layer wasseparated, washed with water and brine, filtered, and evaporated. Theproduct was purified by flash chromatography on silica with ethylacetate/n-heptane (3:7) to give 2.21 g (36%) of the subtitle compound.

APCI-MS: m/z 192.2 [MH⁺-BOC]

Example 307N-((1R,2S)-1-(2,3-dihydrobenzofuran-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-yl)-2,2,2-trifluoroacetamide

To a solution of(1R,2S)-1-(2,3-dihydrobenzofuran-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine(44 mg, 11 μmol) in THF (1.5 mL) was added DIPEA (36 μL, 220 μmol), andthe mixture was stirred for 20 min. Then a solution of trifluoroaceticanhydride (31 μL, 220 μmol) in THF (0.6 ml) was added in 100 μlportions. The mixture was stirred for 2 h. The solvent was removed, andthe row product was partitioned between aq. HCl (1N) and ethyl acetate.The organic layer was dried and submitted to flash chromatography onsilica gel with ethyl acetate/n-heptane (2:3) to give 40 mg (73%) of thetitle compound.

APCI-MS: m/z 500 [MH⁺]

¹H NMR (400 MHz, dmso) δ 9.50 (d, J=8.5 Hz, 1H), 8.18 (s, 1H), 7.74 (m,2H), 7.69 (d, J=9.2 Hz, 1H), 7.40 (dd, J=15.4, 2.3 Hz, 2H), 7.22-7.15(m, 2H), 7.10 (d, J=2.1 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.76 (s, 1H),5.24 (d, J=6.2 Hz, 2H), 4.48 (td, J=8.6, 5.6 Hz, 2H), 4.20 (dd, J=14.7,6.7 Hz, 1H), 3.11 (t, J=8.7 Hz, 2H), 1.31 (d, J=6.7 Hz, 3H)

Example 3082,2,2-trifluoro-N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxy-4-(methylthio)phenyl)propan-2-yl)acetamide

To a stirred solution of(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxy-4-(methylthio)phenyl)propan-2-amine(308a, 32 mg, 70 μmol) in THF (2 mL) was addedN-ethyl-N-isopropylpropan-2-amine (12 μL, 70 μmol), and the mixture wasstirred for 20 min. Then trifluoroacetic anhydride (21 μL, 150 μmol) wasadded, and the mixture was stirred for 2 h. The solvent was removed, andthe crude product was partitioned between aq. HCl (1N) and ethylacetate. The organic layer was dried and purified by HPLC go afford 6 mg(15%) of the title compound.

APCI-MS: m/z 534.1 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (d, J=8.5 Hz, 1H), 8.18 (d, J=0.7 Hz,1H), 7.74 (m 2H), 7.69 (d, J=9.0 Hz, 1H), 7.40 (dd, J=21.1, 3.6 Hz, 2H),7.20 (dd, J=9.1, 2.4 Hz, 1H), 7.15 (d, J=2.1 Hz, 1H), 7.08 (d, J=8.5 Hz,1H), 6.98 (m, 2H), 5.26 (d, J=6.4 Hz, 1H), 4.27 (dd, J=14.9, 6.7 Hz,1H), 3.80 (s, 3H), 2.33 (s, 3H), 1.34 (d, J=6.7 Hz, 3H).

(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxy-4-(methylthio)phenyl)propan-2-amine(308a)

A mixture of(1R,2S)-2-amino-1-(3-methoxy-4-(methylthio)phenyl)propan-1-ol (308b, 17mg, 70 μmol), 1-(4-fluorophenyl)-5-iodo-1H-indazole (30 mg, 90 μmol),and cesium carbonate (73 mg, 220 μmol) in butyronitrile (1 mL) wasstirred for 5 min. Then copper(I) iodide (19 μg, 10 μmmol) was added,and the mixture was stirred at 105° C. for 3 h. After cooling to r.t.the solvent was evaporated under reduced pressure, and the mixture waspartitioned between aq. HCl (1N) and ethyl acetate. The layers wereseparated, the water layer was extracted with ethyl acetate. Thecombined organic extracts were dried, the solvent was removed in vacuoThe residue was purified by HPLC to give 7 mg (21) of the titlecompound.

APCI-MS: m/z 438.1 [MH⁺]

(1R,2R)-2-amino-1-(3-methoxy-4-(methylthio)phenyl)propan-1-ol (308b)

t-Butyl(R)-1-hydroxy-1-(3-methoxy-4-(methylthio)phenyl)propan-2-ylcarbamate(308c, 44 μg, 130 μmol) was dissolved in a solution of HC in ethylacetate (1M, 5 mL) and stirred at 60° C. for 2 h. The solvent wasevaporated, and the diastereomers were separated by HPLC (XBridgecolumn). The subtitle compound is the first eluted product, 17 mg (55%).

APCI-MS: m/z 228.1 [MH⁺]

t-Butyl(2R)-1-hydroxy-1-(3-methoxy-4-(methylthio)phenyl)propan-2-ylcarbamate(308c)

To a stirred solution of (R)-t-butyl1-(3-methoxy-4-(methylthio)phenyl)-1-oxopropan-2-ylcarbamate (308d, 55μg, 170 μmol) in THF (2 mL) at r.t. was added sodium tetrahydroborate(48 μg, 1.27 mmol) in small portions, and the mixture was stirred for 3h.

The mixture was quenched with aq. 1N HCl, and extracted with ethylacetate. The organic layers were dried, the solvent was removed and theresidue was purified by HPLC to give 44 mg (80%) of the subtitlecompound.

APCI-MS: m/z 227.4 [MH⁺-BOC]

(R)-t-Butyl 1-(3-methoxy-4-(methylthio)phenyl)-1-oxopropan-2-ylcarbamate(308d)

Magnesium (17 μg, 0.69 mmol) was placed in a screwcap reaction tube, anda solution of (4-bromo-2-methoxyphenyl)(methyl)sulfane (308e, 100 μg,0.43 mmol) in tetrahydrofuran (1 mL) was added, followed by a smallcrystal of iodine. The tube was sealed and flushed with argon. Themixture was stirred at 60° C. overnight. After cooling (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (35 μg, 150 μmol) wasadded as a solid, and the mixture was stirred at r.t. for 1 h. Then thesolvent was evaporated, the mixture was partitioned between aq. HCl (1N)and ethyl acetate. The organic layer was separated and dried. Theproduct was isolated by HPLC to afford 10 mg (10%).

APCI-MS: m/z 226.2 [MH⁺-BOC]

(4-bromo-2-methoxyphenyl)(methyl)sulfane (308e)

To a solution of 4-bromo-2-methoxybenzenethiol (1.21 g, 5.52 mmol) inDMF (5 mL) was added potassium carbonate (2.29 g, 16.5 mmol) underargon. The resulting mixture was stirred for 10 min, and theniodomethane (3.44 mL, 55.2 mmol) was slowly added over 2 min. Theresulting mixture was stirred at r.t. overnight. Then the reactionmixture was poured into water (75 ml), and extracted with ethyl acetate.The organic layer was dried and the solvent was evaporated, the residuewas purified by flash chromatography on silica gel with n-heptane/ethylacetate (7:3) to give 920 mg (72%) of the subtitle compound.

GC/MS: 234.1

4-Bromo-2-methoxybenzenethiol (308f)

To a stirred solution of potassium carbonate (308 g, 2.44 g, 17.6 mmol)in MeOH (20 mL) was added S4-bromo-2-methoxyphenyldimethylcarbamothioate (0.64 g, 2.21 mmol). The mixture was heated withreflux for 4 h, then cooled on ice bath. Water (20 ml) was added, andthe pH was adjusted to neutral by addition of with aq. HCl (3N). Themixture was extracted with DCM, the organic layers were dried, filtered,and concentrated under reduced pressure to give a light brown liquidwhich was characterized with GC/MS and used without furtherpurification, 440 mg (91%).

GC/MS: 219.1

S-4-bromo-2-methoxyphenyl dimethylcarbamothioate (308g)

O-4-Bromo-2-methoxyphenyl dimethylcarbamothioate (503 mg, 1.73 mmol) wassuspended in N,N-dimethylaniline (2.5 mL), and the reaction mixture washeated in a microwave (240° C., 300 W) for 75 min. The mixture was thendiluted with aq. HCl (3N, 20 mL) and extracted 3 times with ether (30ml). The organic layers were combined, dried, filtered, and purified byHPLC to afford 330 mg (66%) of the subtitle compound.

APCI-MS: m/z 291.8 [MH⁺]

O-4-bromo-2-methoxyphenyl dimethylcarbamothioate (308h)

A mixture of 4-bromoguaiacol (2.05 g, 10.1 mmol) and1,4-diazabicyclo(2.2.2)octane (1.42 g, 12.6 mmol) in NMP (24 mL) washeated at 50° C. to give a dark-yellow solution. A solution ofdimethylthiocarbamoyl chloride (1.37 g, 11.1 mmol) in NMP (2 ml) wasadded dropwise to the previous solution over 1-2 min. Some precipitatedhas formed during the addition. The mixture was stirred at 50° C. for 3h, and then water (25 ml) was added over 5 min at 50° C. The mixture wasstirred overnight at r.t., and the precipitate was isolated byfiltration, washed twice with water, and dried in vacuo at 50° C. toyield a pale creamed-coloured crystalline solid, 2.11 g (72%).

APCI-MS: m/z 291.8 [MH⁺]

Example 309 Human Glucocorticoid Receptor (GR) Assay

The assay is based on a commercial kit from Panvera/Invitrogen (Partnumber P2893). The assay technology is fluorescence polarization. Thekit utilises recombinant human GR (Panvera, Part number P2812), aFluoromone™ labelled tracer (GS Red, Panvera, Part number P2894) and aStabilizing Peptide 10× (Panvera, Part number P2815). The GR andStabilizing Peptide reagents are stored at −70° C. while the GS Red isstored at −20° C. Also included in the kit are 1M DTT (Panvera, Partnumber P2325, stored at −20° C.) and GR Screening buffer 10× (Panvera,Part number P2814, stored at −70° C. initially but once thawed stored atr.t.). Avoid repeated freeze/thaws for all reagents. The GR Screeningbuffer 10× comprises 100 mM potassium phosphate, 200 mM sodiummolybdate, 1 mM EDTA and 20% DMSO.

Test compounds (1 μL) and controls (1 μL) in 100% DMSO were added toblack polystyrene 384-well plates (Greiner low volume black flat-bottom,part number 784076). 0% control was 100% DMSO and 100% control was 10MDexamethasone. Background solution (8 μL; assay buffer 10×, StabilizingPeptide, DTT and ice cold MQ water) was added to the background wells.GS Red solution (7 μL; assay buffer 10×, Stabilizing Peptide, DTT, GSRed and ice cold water) was added to all wells except background wells.GR solution (7 μL; assay buffer 10×, Stabilizing Peptide, DTT, GR andice cold water) was added to all wells. The plate was sealed andincubated in a dark at r.t. for 2 h. The plate was read in an Analystplate reader (LJL Biosystems/Molecular Devices Corporation) or othersimilar plate reader capable of recording fluorescence polarization(excitation wavelength 530 nm, emission wavelength 590 nM and a dichroicmirror at 561 nm). The IC₅₀ values were calculated using XLfit model205.

GRhuFL_FP_v2 Mean IC50 Example (nM)  1 2.3  2 2.7  3 3.2  4 5.9  5 2.1 6 1.8  7 2  8 2.3  9 2  10 2.4  11 2.1  12 2.8  13 5.1  14 3.4  15 6.8 16 2.4  17 12  18 2.8  19 5.2  20 9  21 3.2  22 4.7  23 3.2  24 3.2  2511  26 5.9  27 3.2  28 25  29 6.4  30 6.6  31 2.8  32 7.7  33 18  34 2.4 35 2.1  36 10  37 2.4  38 2.4  39 6.4  40 3.4  41 2.6  42 3  43 2.2  442.7  45 2.6  46 3.4  47 2.5  48 2.9  49 2.8  50 2.9  51 4.3  52 3.1  533.5  54 2.9  55 3.3  56 4.4  57 4.1  58 2.7  59 3.3  60 3.3  61 3.3  623.5  63 4.4  64 3.9  65 3.8  66 4.2  67 4.1  68 1.7  69 76  70 89  714.6  72 3.7  73 5.1  74 3.7  75 5.3  76 2.2  77 2.6  78 3.2  79 2.6  803.7  81 3.5  82 5.3  83 5.8  84 2.3  85 2.1  86 3.8  87 3.4  88 3.2  894.4  90 4.2  91 5.2  92 3.8  93 3.7  94 3.1  95 3.4  96 3.5  97 3.3  983.4  99 3.8 100 9.2 101 15 102 2.5 103 2.6 104 3.6 105 3.2 106 3.7 107 4108 4.9 109 23 110 29 111 15 112 21 113 24 114 3.2 115 3.8 116 7.7 1175.2 118 2.9 119 3.1 120 210 121 2.8 122 2.1 123 4.2 124 2.7 125 6.4 1262.9 127 4 128 3.9 129 11 130 2.5 131 4 132 4.1 133 3.3 134 3.6 135 3.1136 3 137 360 138 3.5 139 4.1 140 3.6 141 3.3 142 5.6 143 23 144 3 1455.5 146 78 147D1E1 97 147D1E2 24 147D2E1 7.4 147D2E2 12 148 280 149 5.5150 4.6 151 32 152 3.6 153 3.6 154 4.7 155 5 156 4.2 157 5.3 158 3.4 1594.2 160 4.1 161 8.5 162 14 163 16 164 4.2 165 6.4 166 6.9 167 8.6 1686.2 169 8.1 170 7.1 171 5.6 172 4.3 173 4.6 174 4.1 175 4.3 176 4.9 1773.9 178 3.9 179 3.7 180 6.8 181 3.2 182 5.5 183 4.6 184 5.1 185 5.5 1866.6 187 4.5 188 7.3 189 7.8 190 4.5 191 5.9 192 4.3 193 6.5 194 3.9 1953.3 196 6.2 197 4.9 198 3.8 199 7.4 200 4.6 201 5.9 202 5.3 203 5.4 2046.7 205 6.6 206 7.5 207 8.8 208 8.2 209 4.1 210 5.2 211 3 212 5.2 2134.4 214 4.5 215 4.4 216 4.7 217 3.9 218 3.3 219 2.8 220 4.2 221 4.4 2223.5 223 3.9 224 5.7 225 4.8 226 7.2 227 3.1 228 8 229 5.5 230 4.8 2315.1 232 5.4 233 6.1 234 6.4 235 5.4 236 7.2 237 8.4 238 6.8 239 9 2405.9 241 4.9 242 5.5 243 5.5 244 8.3 245 5.5 246 6 247 4.4 248 4.8 249 5250 6.9 251 5.3 252 4.7 253 7.5 254 8.5 255 5.1 256 5.3 257 13 258 4.4259 5.3 260 14 261 5.7 262 4.5 263 4.2 264 6.5 265 25 266 2.9 267 3.7268 3.1 269 12 270 8.1 271 21 272 4.3 273 7.9 274 3.9 275 4 276 12 2774.7 278 3.4 279 3.8 280 3.6 281 3.8 282 2.4 283 4.7 284 22 285 3.5 2864.7 287 4.3 288 5 289 3.9 290 3.1 291 6.4 292 5.7 293 4.4 294 4.1 2955.7 296 4 297 8.6 298 15 299 3.1 300 2.4 301 5.2 302 3.2 303 5 304 7.5305 8.3 306 2.5 307 4.8 308 6.9

1. A compound

or a pharmaceutically acceptable salt thereof.
 2. A mixture ofN-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]cyclopropanecarboxamide,or a pharmaceutically acceptable salt thereof; andN-[(1S,2R)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]cyclopropanecarboxamide,or a pharmaceutically acceptable salt thereof.
 3. The mixture accordingto claim 2, wherein the mixture is a racemic mixture. 4.N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]cyclopropanecarboxamide,or a pharmaceutically acceptable salt thereof.
 5. The compound accordingto claim 4, which isN-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]cyclopropanecarboxamide.6. The compound according to claim 4, which isN-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxypyridin-3-yl)propan-2-yl]cyclopropanecarboxamidein the form of a pharmaceutically acceptable salt.
 7. A pharmaceuticalcomposition comprising a compound or a pharmaceutically acceptable saltthereof as claimed in claim 1, and a pharmaceutically acceptableadjuvant, diluent or carrier.
 8. A pharmaceutical composition comprisinga mixture as claimed in claim 2 or 3, and a pharmaceutically acceptableadjuvant, diluent or carrier.
 9. A pharmaceutical composition comprisinga compound or a pharmaceutically acceptable salt thereof as claimed inclaim 4, and a pharmaceutically acceptable adjuvant, diluent or carrier.10. A pharmaceutical composition comprising a compound as claimed inclaim 5, and a pharmaceutically acceptable adjuvant, diluent or carrier.11. A method of treating asthma, which comprises administering to amammal that has asthma and is in need of treatment for asthma aneffective amount of a compound or a pharmaceutically acceptable saltthereof as claimed in claim
 1. 12. A method of treating COPD, whichcomprises administering to a mammal that has COPD and is in need oftreatment for COPD an effective amount of a compound or apharmaceutically acceptable salt thereof as claimed in claim 1.